Indoles having anti-diabetic activity

ABSTRACT

Indoles having aryloxyalkanoic acid substituents or arylalkanoic acid substituents are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.

FIELD OF THE INVENTION

The instant invention is concerned with indoles having anaryloxyalkanoic acid substituent, and pharmaceutically acceptable saltsand prodrugs thereof, which are useful as therapeutic compounds,particularly in the treatment of Type 2 diabetes mellitus, and ofconditions that are often associated with this disease, includingobesity and lipid disorders.

BACKGROUND OF THE INVENTION

Diabetes is a disease derived from multiple causative factors andcharacterized by elevated levels of plasma glucose (hyperglycemia) inthe fasting state or after administration of glucose during an oralglucose tolerance test. There are two generally recognized forms ofdiabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), patients produce little or no insulin, the hormone whichregulates glucose utilization. In type 2 diabetes, ornoninsulin-dependent diabetes mellitus (NIDDM), insulin is stillproduced in the body. Patients having type 2 diabetes often havehyperinsulinemia (elevated plasma insulin levels); however, thesepatients are insulin resistant, which means that they have a resistanceto the effect of insulin in stimulating glucose and lipid metabolism inthe main insulin-sensitive tissues, which are muscle, liver and adiposetissues. Patients who are insulin resistant but not diabetic compensatefor the insulin resistance by secreting more insulin, so that serumglucose levels are not elevated enough to meet the criteria of Type 2diabetes. In patients with Type 2 diabetes, even elevated plasma insulinlevels are insufficient to overcome the pronounced insulin resistance.

Persistent or uncontrolled hyperglycemia that occurs with diabetes isassociated with increased and premature morbidity and mortality. Oftenabnormal glucose homeostasis is associated both directly and indirectlywith obesity, hypertension, and alterations of the lipid, lipoproteinand apolipoprotein metabolism, as well as other metabolic andhemodynamic disease. Patients with type 2 diabetes mellitus have asignificantly increased risk of macrovascular and microvascularcomplications, including atherosclerosis, coronary heart disease,stroke, peripheral vascular disease, hypertension, nephropathy,neuropathy, and retinopathy. Therefore, therapeutic control of glucosehomeostasis, lipid metabolism, obesity, and hypertension are criticallyimportant in the clinical management and treatment of diabetes mellitus.

Many patients who have insulin resistance or Type 2 diabetes often haveseveral symptoms that together are referred to as syndrome X, or themetabolic syndrome. A patient having this syndrome is characterized ashaving three or more symptoms selected from the following group of fivesymptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) lowhigh-density lipoprotein cholesterol (HDL); (4) high blood pressure; and(5) elevated fasting glucose, which may be in the range characteristicof Type 2 diabetes if the patient is also diabetic. Each of thesesymptoms is defined in the recently released Third Report of theNational Cholesterol Education Program Expert Panel on Detection,Evaluation and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III, or ATP III), National Institutes of Health, 2001,NIH Publication No. 01-3670. Patients with metabolic syndrome, whetheror not they have or develop overt diabetes mellitus, have an increasedrisk of developing the macrovascular and microvascular complicationsthat are listed above that occur with type 2 diabetes, such asatherosclerosis and coronary heart disease.

Insulin resistance is not primarily caused by a diminished number ofinsulin receptors but by a post-insulin receptor binding defect that isnot yet completely understood. This lack of responsiveness to insulinresults in insufficient insulin-mediated activation of uptake, oxidationand storage of glucose in muscle and inadequate insulin-mediatedrepression of lipolysis in adipose tissue and of glucose production andsecretion in the liver.

There are several available treatments for type 2 diabetes, each ofwhich has its own limitations and potential risks. Physical exercise anda reduction in dietary intake of calories often dramatically improve thediabetic condition and are the best first line treatment of type 2diabetes. Compliance with this treatment is very poor because ofwell-entrenched sedentary lifestyles and excess food consumption,especially of foods containing high amounts of fat. A widely used drugtreatment involves the administration of meglitinide or a sulfonylurea(e.g. tolbutamide or glipizide), which are insulin secretagogues. Thesedrugs increase the plasma level of insulin by stimulating the pancreaticβ-cells to secrete more insulin. When administration of a sulfonylureaor meglitinide becomes ineffective, the amount of insulin in the bodycan be supplemented by the injection of insulin so that insulinconcentrations are high enough to stimulate even the veryinsulin-resistant tissues. However, dangerously low levels of plasmaglucose can result from administration of insulin and/or insulinsecretagogues, and an increased level of insulin resistance due to theeven higher plasma insulin levels can occur.

The biguanides are another class of drugs that are widely used to treattype 2 diabetes. The two best known biguanides, phenformin andmetformin, cause some correction of hyperglycemia without risk ofcausing hypoglycemia. The biguanides can be used either with insulin orwith an insulin secretagogue without increasing the risk ofhypoglycemia. However, phenformin and metformin can induce lacticacidosis and nausea/diarrhea. Metformin has a lower risk of side effectsthan phenformin and is widely prescribed for the treatment of Type 2diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer classof compounds that can ameliorate hyperglycemia and other symptoms oftype 2 diabetes. These agents substantially increase insulin sensitivityin muscle, liver and adipose tissue in several animal models of type 2diabetes, resulting in partial or complete correction of elevated plasmaglucose levels without the occurrence of hypoglycemia. The glitazonesthat are currently marketed (rosiglitazone and pioglitazone) areagonists of the peroxisome proliferator activated receptor (PPAR) gammasubtype. PPAR-gamma agonism is generally believed to be responsible forthe improved insulin sensititization that is observed with theglitazones. New PPAR agonists are being developed for the treatment ofType 2 diabetes and/or dyslipidemia. Many of the newer PPAR compoundsare agonists of one or more of the PPAR alpha, gamma and delta subtypes.Compounds that are agonists of both the PPAR alpha and PPAR gammasubtypes (PPAR alpha/gamma dual agonists) are promising because theyreduce hyperglycemia and also improve lipid metabolism.

PPAR agonists, and particularly glitazones, have had shortcomings whichhave so far detracted from their attractiveness. Some of the compounds,and especially troglitazone, have exhibited liver toxicity. Troglitazonewas eventually withdrawn from the marketplace because of hepatotoxicity.Another weakness in the currently marketed PPAR agonists is thatmonotherapy for type 2 diabetes produces only modest efficacy—areduction in average plasma glucose of ≈20% and a decline from ≈9.0% to≈8.0% in HemoglobinA1C. The current compounds also do not greatlyimprove lipid metabolism, and may actually have a negative effect on thelipid profile. These shortcomings have provided an incentive to developbetter insulin sensitizers for Type 2 diabetes which function viasimilar mechanism(s) of action.

Recently, there have been reports of compounds that are PPAR gammaantagonists or partial agonists. WO01/30343 describes a specificcompound that is a PPAR partial agonist/antagonist that is useful forthe treatment of obesity and Type 2 diabetes. WO02/08188 discloses aclass of PPAR agonists and partial agonists that are indole derivativesand that are useful in the treatment of Type 2 diabetes, with reducedside effects relating to body and heart weight gain.

SUMMARY OF THE INVENTION

The class of compounds described herein is a new class of PPAR agoniststhat do not contain a 1,3-thiazolidinedione moiety. The class ofcompounds includes many compounds that are PPARγ partial agonists, butalso may include PPARγ full agonists and/or PPARγ antagonists. Somecompounds may also have PPARα activity in addition to PPARγ activity.Some compounds may be mixed full or partial PPARα/γ agonists. Thesecompounds are useful in the treatment and control of diabetes,hyperglycemia, and insulin resistance.

The compounds may also be useful in the treatment of one or more lipiddisorders, including mixed or diabetic dyslipidemia, isolatedhypercholesterolemia, which may be manifested by elevations in LDL-Cand/or non-HDL-C, hyperapoBliproteinemia, hypertriglyceridemia, anincrease in triglyceride-rich-lipoproteins, and low HDL cholesterolconcentrations. They may also be useful in the treatment or ameliorationof atherosclerosis, obesity, vascular restenosis, inflammatoryconditions, psoriasis, polycystic ovary syndrome, and other PPARmediated diseases, disorders and conditions.

The present invention is directed to compounds of formula I:

and pharmaceutically acceptable salts and prodrugs thereof.

In the compounds of formula I,

-   -   R¹ is selected from        -   (a) —X-Aryl-Y-Z, and        -   (b) —X-Heteroaryl-Y-Z,        -   where Aryl and Heteroaryl are unsubstituted or substituted            with 1-3 groups independently selected from A;    -   Aryl is phenyl or naphthyl;    -   Heteroaryl is a monocyclic or fused bicyclic aromatic ring        structure containing 1-4 heteroatoms independently selected from        N, O, and S(O)_(n); (Note that S(O) and S(O)₂ are included in        the ring structure through the S atom, and that Heteroaryl may        be a benzene ring that is fused to an aromatic heterocycle, such        as occurs in indole.);    -   X is a bond or a divalent group selected from CH₂, CH(CH₃),        C(CH₃)₂, and C₃-C₆cycloalkylidene;    -   Y is a divalent group selected from —CH═CH—, —CH(OH)CH(OH)—,        —OCR⁷R⁸—, —CR⁷R⁸—, and —CH₂CR⁵R⁶—;    -   Z is selected from the group consisting of —CO₂H and tetrazole;    -   A is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄        alkenyl, —OC₁₋₄ alkyl, and halogen, wherein alkyl, alkenyl, and        —Oalkyl are each optionally substituted with 1-5 halogens;    -   R⁵, R⁶, R⁷, and R⁸ are each independently selected from the        group consisting of H, halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl,        C₂-C₅ alkenyl, —OC₂-C₅ alkenyl, C₃₋₆ cycloalkyl, phenyl, and        —CO₂H, wherein C₁-C₅ alkyl, —OC₁-C₅ alkyl, C₂-C₅ alkenyl,        —OC₂-C₅ alkenyl, C₃₋₆ cycloalkyl, and phenyl are optionally        substituted with 1-5 halogens, and C₃₋₆ cycloalkyl and phenyl        are further optionally substituted with 1-3 groups independently        selected from C₁-C₃ alkyl and —OC₁-C₃ alkyl, said C₁-C₃ alkyl        and —OC₁-C₃ alkyl being optionally substituted with 1-3        halogens;    -   Or alternatively R⁷ and R⁸ may be joined to form a C₃-C₆        cycloalkyl group, said C₃-C₆ cycloalkyl group being optionally        substituted with 1-3 halogens;    -   Or alternatively, when R¹ is —X-Phenyl-Y-Z, Y is —OCR⁷R⁸, and R⁷        is selected from the group consisting of H, halogen, C₁-C₅        alkyl, —OC₁-C₅ alkyl, C₂₋₅ alkyl, —OC₂₋₅ alkyl, C₃₋₆ cycloalkyl,        and phenyl, then R⁸ may optionally be a 1-2-carbon bridge        connected to the phenyl ring at the position ortho to Y, thereby        yielding a 5 or 6-membered heterocyclic ring fused to the phenyl        ring;    -   R² is C₁-C₄ alkyl, which is optionally substituted with 1-5        halogens;    -   R³ is selected from the following substituent groups:        -   (a) benzisoxazolyl,        -   (b) benzisothiazolyl,        -   (c) benzpyrazolyl,        -   (d) Aryl,        -   (e) —C(═O)Aryl,        -   (f) —C(═O)Heteroaryl,        -   (g) —OAryl,        -   (h) —OHeteroaryl,        -   (i) —S(O)_(n)Aryl, and        -   (j) —S(O)_(n)Heteroaryl,        -   wherein R³ is optionally substituted with 1-3 substituent            groups independently selected from halogen, C₁₋₃alkyl,            —OC₁₋₃alkyl, and —SC₁₋₃alkyl, wherein C₁₋₃alkyl,            —OC₁₋₃alkyl, and —SC₁₋₃alkyl are optionally substituted with            1-5 halogens;    -   each R⁴ is optionally selected from H, halogen, C₁-C₅ alkyl and        —OC₁-C₅ alkyl, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are        optionally substituted with 1-5 halogens;    -   n is an integer from 0-2; and    -   p is an integer from 1 to 3.

In the above definitions and subsequent definitions, alkyl groups may beeither linear or branched, unless otherwise specified.

The present compounds are effective in lowering glucose, lipids, andinsulin in diabetic patients and in non-diabetic patients that haveimpaired glucose tolerance and/or are in a pre-diabetic condition. Thecompounds are expected to be efficacious in the treatment of non-insulindependent diabetes mellitus (NIDDM) in human and other mammalianpatients, particularly in the treatment of hyperglycemia and in thetreatment of conditions associated with NIDDM, including hyperlipidemia,dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia,atherosclerosis, vascular restenosis, inflammatory conditions, and otherPPAR mediated diseases, disorders and conditions.

DETAILED DESCRIPTION OF THE INVENTION

The invention has numerous embodiments. It provides compounds of formulaI, including pharmaceutically acceptable salts of these compounds,prodrugs of these compounds, and pharmaceutical compositions comprisingthese compounds and a pharmaceutically acceptable carrier.

In preferred embodiments, R³ is selected from the group consisting of3-benzisoxazolyl, —O-Phenyl, and —C(═O)Phenyl, wherein R³ is optionallysubstituted with 1-3 substituents independently selected from halogen,—OC₁-C₃alkyl, and C₁₋₃alkyl, wherein said —OC₁-C₃alkyl and C₁-C₃alkylare optionally substituted with 1-5 halogens.

In preferred embodiments of the invention, R¹ is —X-Phenyl-Y-Z, wherePhenyl is unsubstituted or substituted with 1-3 groups independentlyselected from A.

A subset of compounds of Formula I includes compounds in which X is abond.

A subset of compounds of Formula I includes compounds in which X is CH₂.

In a desirable subset of compounds, Y is —OCR⁷R⁸—, R⁷ is selected fromthe group consisting of H and C₁-C₃ alkyl, and R⁸ is C₁-C₃ alkyl, whereR⁷ and R⁸ are optionally substituted with 1-3 halogens.

In another desirable subset of compounds, Y is —OCR⁷R⁸—, R⁷ is selectedfrom H and C₁-C₃ alkyl, and R⁸ is C₁-C₃ alkyl.

In another useful set of compounds, Y is —CH₂CHR⁶—, where R⁶ is selectedfrom C₁₋₃alkyl and —OC₁₋₃ alkyl, which are optionally substituted with1-3 halogens.

In another set of compounds, Y is —CH₂CHR⁶—, where R⁶ is —OC₁₋₃ alkyl,which is optionally substituted with 1-3 halogens.

In preferred embodiments, A is selected from the group consisting ofC₁-C₃alkyl, CF₃, —OCH₃, —OCF₃, and halogen.

A preferred subset of compounds includes compounds in which R² is C₁₋₃alkyl or CF₃.

In many preferred compounds, R³ is —C(═O)Phenyl, where R³ is optionallysubstituted with 1-3 substituents independently selected from —OCH₃,—OCF₃, and halogen.

In other useful compounds, R³ is 3-benzisoxazolyl or aryl, which isoptionally substituted with 1-3 substituents independently selected fromhalogen, OCH₃, OCF₃, CH₃, and CF₃.

In another subset of compounds, R³ is 3-benzisoxazolyl, aryl, —OPhenyl,or —SPhenyl, where R³ is optionally substituted with 1 substituentselected from halogen, OCH₃, OCF₃, and CF₃.

In another subset of compounds, R¹ is —X-Pyridinyl-Y-Z.

A subset of compounds includes compounds in which p is 1.

Preferred compounds generally have a group Z which is —CO₂H.

In preferred sets of compound, R¹ is generally

where X is selected from the group consisting of a bond, CH₂, CH(CH₃),C(CH₃)₂, and C₃-C₆cycloalkylidene;

-   -   Y is selected from the group consisting of —OCR⁷R⁸— and        CH₂CR⁵R⁶;    -   Z is selected from —CO₂H and tetrazole;    -   A is selected from C₁-C₃ alkyl, CF₃, —OCH₃, —OCF₃, and halogen;    -   R⁵, R⁶, and R⁷are each independently selected from the group        consisting of H, halogen, C₁-C₃ alkyl, and —OC₁-C₃ alkyl, and R⁸        is selected from the group consisting of halogen, C₁-C₃ alkyl,        and —OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and —OC₁-C₃ alkyl of R⁵,        R⁶, R⁷, and R⁸ are each optionally substituted with 1-3        halogens;    -   q is an integer from 0-3;    -   p is 1;    -   R² is selected from CF₃ and C₁-C₃ alkyl;    -   R³ is selected from the group consisting of        -   (a) 3-benzisoxazolyl,        -   (b) 3-benzisothiazolyl,        -   (c) 3-benzpyrazolyl,        -   (d) Aryl        -   (e) —C(═O)Phenyl,        -   (f) —C(═O)Heteroaryl,        -   (g) —OPhenyl,        -   (h) —OHeteroaryl,        -   (i) —S(O)_(n)Phenyl, and        -   (j) —S(O)_(n)Heteroaryl,            -   wherein Heteroaryl is selected from the group consisting                of pyridyl and quinolyl,            -   n is an integer from 0-2, and            -   R³ is optionally substituted with 1-3 groups                independently selected from halogen, —OC₁-C₃alkyl, and                C₁₋₃alkyl, wherein said —OC₁-C₃alkyl and C₁-C₃alkyl are                optionally substituted with 1-5 halogens.

A desirable subset of the compounds described immediately above have thefollowing substituents:

-   -   X is a bond or CH₂;    -   Y is —OCR⁷R⁸— or —CH₂CR⁵R⁶—;    -   Z is —CO₂H;    -   A is selected from CH₃, CF₃, —OCH₃, —OCF₃, and halogen;    -   R⁵ is H;    -   R⁶ is selected from the group consisting of H, C₁-C₃ alkyl, and        —OC₁-C₃ alkyl, wherein C₁-C₃ alkyl and —OC₁-C₃ alkyl are        optionally substituted with 1-3 halogens;    -   R⁷ is selected from the group consisting of H and C₁-C₃ alkyl;    -   R⁸ is C₁-C₃ alkyl;    -   R² is CH₃;    -   R³ is selected from the group consisting of        -   (a) 3-benzisoxazolyl,        -   (b) Aryl,        -   (c) —C(═O)Phenyl,        -   (d) —C(═O)Pyridyl, and        -   (e) —C(═O)Quinolyl,        -   wherein R³ is optionally substituted with 1-3 groups            independently selected from halogen, —OC₁-C₃alkyl, and            C₁₋₃alkyl, wherein said —OC₁-C₃alkyl and C₁-C₃alkyl are            optionally substituted with 1-5 halogens; and    -   q is an integer from 0-3.

In preferred groups of the above compounds, Y is —OCR⁷R⁸—, R⁷ is H, andR⁸ is C₁₋₃alkyl, which is optionally substituted with 1-3 halogens.

In other preferred groups of the above compounds, Y is —CH₂CR⁵R⁶—, R⁵ isH, and R⁶ is C₁₋₃alkyl or —OC₁₋₃ alkyl, where C₁₋₃ alkyl and —OC₁₋₃alkyl are optionally substituted with 1-3 halogen atoms.

In preferred compounds, the X and —YZ substitutents on the phenyl groupabove are meta or para to one another, and in more preferred compounds,X and —YZ are meta with respect to one another, as shown below asFormula IA.

Compounds having Formula IA as shown below, and pharmaceuticallyacceptable salts thereof, have especially useful properties in treatinginsulin resistance, type 2 diabetes, and dyslipidemia that is associatedwith type 2 diabetes and insulin resistance:

In the compounds of Formula IA, X is a bond or CH₂;

-   -   Y is —OC*R⁷R⁸— or —CH₂C*R⁵R⁶—;    -   Z is —CO₂H;    -   A is selected from CH₃, CF₃, —OCH₃, —OCF₃, and halogen;    -   q is 0 or 1;    -   R⁴ is C₁₋₃alkyl, CF₃, —OCH₃, or —OCF₃;    -   p is 0 or 1;    -   R⁵ is selected from H and C₁-C₃ alkyl, wherein C₁-C₃ alkyl is        optionally substituted with 1-3 halogens;    -   R⁶ is C₁-C₃ alkyl or —OC₁-C₃ alkyl, wherein C₁-C₃ alkyl, and        —OC₁-C₃ alkyl are optionally substituted with 1-3 halogens;    -   R⁷ is selected from the group consisting of H and C₁-C₃ alkyl,        which is optionally substituted with 1-3 halogens;    -   R⁸ is C₁-C₃ alkyl, which is optionally substituted with 1-3        halogens;    -   R² is CH₃; and    -   R³ is selected from the group consisting of        -   (a) 3-benzisoxazolyl,        -   (b) —O-Phenyl, and        -   (c) —C(═O)Phenyl,    -   where R³ is optionally substituted with 1-3 groups independently        selected from halogen, —OC₁-C₃alkyl, and C₁₋₃alkyl, wherein said        —OC₁-C₃alkyl and C₁-C₃alkyl are optionally substituted with 1-5        halogens.

In a subset of the compounds described immediately above, p is 1.

The carbon atom which is indicated with an asterisk (C*) in thestructures above, when Y is —OC*H(R⁸)— or —CH₂C*H(R⁶)—, is an asymmetriccarbon. Generally, both the R and S stereochemical configurations at thecarbon C* are active, though they have somewhat different activities interms of the amount of PPARα and PPARγ activity.

Preferred sets of compounds of Formula IA in which X is a bond have thefollowing substituents:

-   -   Y is —OC*R⁷R⁸—;    -   R⁴ is CH₃, CF₃, —OCH₃, or —OCF₃;    -   p is 0 or 1;    -   R⁷ is H; and    -   R⁸ is C₁-C₃ alkyl, which is optionally substituted with 1-3        halogens.

These compounds have an asymmetric center on the carbon of Y. Compoundshaving the R and S stereochemical configuration at C* are active PPARagonists, though they have somewhat different activities in terms of therelative amounts of PPARα and PPARγ activity.

In another preferred subset of compounds of formula IA, X is CH₂;

-   -   Y is —OC*R⁷R⁸—;    -   R⁴ is CH₃, CF₃, —OCH₃, or —OCF₃;    -   p is 0 or 1;    -   R⁷ is H; and    -   R⁸ is C₁-C₃ alkyl, which is optionally substituted with 1-3        halogens.

These compounds also have an asymmetric center on the carbon of Y.Compounds having the R and S stereochemical configuration at C* areactive PPAR agonists, though they have somewhat different activities interms of the relative amounts of PPARα and PPARγ activity.

In other preferred subsets of compounds of Formula IA, where X is eitherCH₂ or a bond, R³ is —C(═O)Phenyl, which is optionally substituted with1-2 groups independently selected from the group consisting of Cl, CH₃,CF₃, —OCH₃, and —OCF₃.

In a subset of the compounds above, p is 1.

Structures of specific compounds are disclosed in Tables 1-4. The namesare provided for the compounds in separate Tables 1A-4A. Each compoundis given the same number in the two sets of tables. Each compound is aspecific embodiment of the current invention. The syntheses of some ofthese compounds are also provided in the Examples.

The compounds of this invention can be used in pharmaceuticalcompositions comprising the compound or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier. The compounds ofthis invention can also be used in pharmaceutical compositions in whicha compound of Formula I or a pharmaceutically acceptable salt thereof isthe only active ingredient.

The compounds of the invention and pharmaceutically acceptable saltsthereof can be used in the manufacture of medicaments for the treatmentof type 2 diabetes mellitus in a human or other mammalian patient.

Some of the compounds of this invention were disclosed in a provisionalapplication which was filed after the filing dates of the two U.S.Provisional Applications from which priority is claimed in thisapplication, to illustrate the use of these compounds in the inventiondisclosed in the later application. The seven compounds are listed belowaccording to where they are disclosed herein:

-   -   1. Tables 1 and 1A, Compound 1    -   2. Tables 1 and 1A, Compound 10    -   3. Tables 2 and 2A, Compound 8; also Example 31    -   4. Tables 2 and 2A, Compound 25    -   5. Tables 3 and 3A, Compound 29    -   6. Tables 3 and 3A, Compound 60; also Example 29    -   7. Tables 3 and 3A, Compound 78

It is to be understood that the invention herein includes the genericclaims as written, and furthermore includes each of the generic claimswith a disclaimer of one or more of the seven compounds listed above.Such a disclaimer may be made during examination. The compoundsthemselves are also claimed.

The compounds as defined above may be used in the following methods totreat diseases, as well as other diseases not listed below:

(1) a method for treating non-insulin dependent diabetes mellitus (type2 diabetes) in a human or other mammalian patient in need of suchtreatment which comprises administering to the patient a therapeuticallyeffective amount of a compound of Formula I;

(2) a method for treating or controlling hyperglycemia in a human orother mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

(3) a method for treating or controlling the metabolic syndrome in ahuman or other mammalian patient in need of such treatment whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula I;

(4) a method for treating or controlling obesity in a human or othermammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

(5) a method for treating or controlling hypercholesterolemia in a humanor other mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

(6) a method for treating or controlling hypertriglyceridemia in a humanor other mammalian patient in need of such treatment which comprisesadministering to the patient a therapeutically effective amount of acompound of Formula I;

(7) a method for treating or controlling one or more lipid disorders,including mixed or diabetic dyslipidemia, low HDL cholesterol, high LDLcholesterol, hyperlipidemia, hypercholesterolemia, andhypertriglyceridemia in a human or other mammalian patient in need ofsuch treatment which comprises administering to the patient atherapeutically effective amount of a compound of Formula I;

(8) a method for reducing the risks of adverse sequelae associated withmetabolic syndrome in a human or other mammalian patient in need of suchtreatment which comprises administering to the patient a therapeuticallyeffective amount of a compound of Formula I; and

(9) a method for treating atherosclerosis, for reducing the risk ofdeveloping atherosclerosis, for delaying the onset of atherosclerosis,and/or reducing the risk of sequelae of atherosclerosis in a human orother mammalian patient in need of such treatment or at risk ofdeveloping atherosclerosis or sequelae of atherosclerosis, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of Formula I. Sequelae of atherosclerosis includefor example angina, claudication, heart attack, stroke, etc.

The compounds are especially useful in the treatment of the followingdiseases, by administering a therapeutically effective amount to apatient in need of treatment:

(1) type 2 diabetes, and especially hyperglycemia;

(2) metabolic syndrome;

(3) obesity; and

(4) hypercholesterolemia;

DEFINITIONS

“Ac” is acetyl, which is CH₃C(O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means mono- or bicyclic saturated carbocyclic rings, eachhaving from 3 to 10 carbon atoms, unless otherwise stated. The term alsoincludes a monocyclic ring fused to an aryl group. Examples ofcycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,and the like.

A cycloalkylidene group is a divalent cycloalkane radical in which bothattachments are at the same carbon. For example, the cyclopropyl groupof 1,1-dimethylcyclopropane is a cyclopropylidene group.

“Aryl” (and “arylene”) when used to describe a substituent or group in astructure means a monocyclic, bicyclic or tricyclic compound in whichall the rings are aromatic and which contains only carbon ring atoms.The term “aryl” can also refer to an aryl group that is fused to acycloalkyl or heterocycle. “Heterocyclyl,” “heterocycle,” and“heterocyclic” means a fully or partially saturated monocyclic, bicyclicor tricyclic ring system containing at least one heteroatom selectedfrom N, S and O, each of said rings having from 3 to 10 atoms. Examplesof aryl substituents include phenyl and naphthyl. Aryl rings fused tocycloalkyls are found in indanyl, indenyl, and tetrahydronaphthyl.Examples of aryl fused to heterocyclic groups are found in2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like.Examples of heterocycles include tetrahydrofuran, piperazine, andmorpholine. Preferred aryl groups are phenyl or naphthyl. Phenyl isgenerally the most preferred.

“Heteroaryl” (and heteroarylene) means a mono-, bi- or tricyclicaromatic ring containing at least one ring heteroatom selected from N, Oand S (including SO and SO₂), with each ring containing 5 to 6 atoms.Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl,pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (includingS-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl,isoquinolyl, dibenzofuran and the like.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“Me” represents methyl.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

The substituent “tetrazole” means a 2H-tetrazol-5-yl substituent groupand tautomers thereof.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein may contain olefinic doublebonds, and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist with different pointsof attachment of hydrogen, referred to as tautomers. An example is aketone and its enol form, known as keto-enol tautomers. The individualtautomers as well as mixtures thereof are encompassed with compounds ofFormula I.

Compounds of the Formula I having one or more asymmetric centers may beseparated into diastereoisomers, enantiomers, and the like by methodswell known in the art.

Alternatively, enantiomers and other compounds with chiral centers maybe synthesized by stereospecific synthesis using optically pure startingmaterials and/or reagents of known configuration.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Metabolites—Prodrugs

Therapeutically active metabolites of other compounds, where themetabolites themselves fall within the scope of the claimed invention,are also compounds of the current invention. Prodrugs, which arecompounds that are converted to the claimed compounds as they are beingadministered to a patient or after they have been administered to apatient, are also compounds of this invention. A non-limiting example ofa prodrug of the carboxylic acids of this invention would be an ester ofthe carboxylic acid group, for example a C₁ to C₆ ester, which may belinear or branched, which metabolizes to a carboxylic acid of thisinvention. An ester which has functionality that makes it more easilyhydrolyzed after administration to a patient may also be a prodrug.

Prodrugs of the class of compounds of this invention may be described ascompounds having the Formula I, wherein Z is a group that is easilymetabolized under physiological conditions during or afteradministration to a mammalian or human patient to yield a compound whereZ is a carboxylic acid group, or a salt thereof (in solution).

Examples of prodrugs of Formula I include compounds in which Z is—CO₂R^(a), where the OR^(a) group can be —OR^(b), —OCH₂OR^(b),—OCH(CH₃)OR^(b), —OCH₂OC(O)R^(b), —OCH(CH₃)OC(O)R^(b), —OCH₂OC(O)OR^(b),and —OCH(CH₃)OC(O)OR^(b), where OR^(b) is selected from C₁₋₆ alkyloptionally substituted with one or two groups selected from —CO₂H,—CONH₂, —NH₂, —OH, —OAc, —NHAc, and phenyl.

Utilities

Compounds of the present invention are potent ligands having agonist,partial agonist or antagonist activity on one or more of the variousperoxisome proliferator activated receptor subtypes, particularly PPARγ.The compounds may also be ligands or agonists, partial agonists orantagonists of the PPARα subtype as well as the PPARγ subtype, resultingin mixed PPARα/γ agonism or in agonism of mainly the PPARα subtype. Somecompounds (generally less preferred) may also be PPARδ ligands and havePPARδ activity in addition to their other PPAR activity. The compoundsof this invention are useful in treating or controlling diseases,disorders or conditions which are mediated by one or more ligands of theindividual PPAR subtypes (e.g. γ or α) or a combination of PPAR subtypes(e.g. α/γ). One aspect of the present invention provides a method forthe treatment and control of diseases that can be mediated byadministration of a PPAR agonist or partial agonist, such as type 2diabetes. One aspect of the present invention provides a method for thetreatment and control of such diseases, disorders, or conditions in amammal which comprises administering to such mammal a therapeuticallyeffective amount of a compound of Formula I. Compounds of the presentinvention may be useful in treating or controlling many PPAR mediateddiseases and conditions, including, but not limited to, (1) diabetesmellitus, and especially non-insulin dependent diabetes mellitus(NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) insulinresistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8)hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia,(11) low HDL levels, (12) high LDL levels, (13) atherosclerosis and itssequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (17) other inflammatory conditions, (18) pancreatitis, (19)abdominal obesity, (20) neurodegenerative disease, (21) retinopathy,(22) psoriasis, (23) metabolic syndrome, (24) ovarian hyperandrogenism(polycystic ovarian syndrome), and other disorders where insulinresistance is a component. They may also have utility in treating highblood pressure, neoplastic conditions, adipose cell tumors, adipose cellcarcinomas, such as liposarcoma, prostate cancer and other cancers,including gastric, breast, bladder and colon cancers, angiogenesis, andAlzheimer's disease.

The compounds may also have utility in treating osteoporosis. Thecompounds of this invention may treat osteoporosis or reduce the risk ofdeveloping osteoporosis by slowing or stopping the loss of bone densityin a patient who has osteoporosis or is at risk of developingosteoporosis. The compounds of this invention may also reverse the lossof bone mass in patients who have already begun to lose bone mass.

One aspect of the invention provides a method for the treatment andcontrol of mixed or diabetic dyslipidemia, hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/orhypertriglyceridemia, which comprises administering to a patient in needof such treatment a therapeutically effective amount of a compoundhaving formula I. The compound may be used alone or advantageously maybe administered with a cholesterol biosynthesis inhibitor, particularlyan HMG-CoA reductase inhibitor such as lovastatin, simvastatin,rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,itavastatin, or ZD-4522. The compound may also be used advantageously incombination with other lipid lowering drugs such as cholesterolabsorption inhibitors (for example stanol esters, sterol glycosides suchas tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (suchas avasimibe), CETP inhibitors, niacin, bile acid sequestrants,microsomal triglyceride transport inhibitors, and bile acid reuptakeinhibitors. These combination treatments may also be effective for thetreatment or control of one or more related conditions selected from thegroup consisting of hypercholesterolemia, atherosclerosis,hyperlipidemia, hypertriglyceridemia, dyslipidemia, high LDL, and lowHDL.

Another aspect of the invention provides a method of treatinginflammatory conditions, including inflammatory bowel disease, Crohn'sdisease, and ulcerative colitis by administering an effective amount ofa compound of this invention to a patient in need of treatment.Additional inflammatory diseases that may be treated with the instantinvention include gout, rheumatoid arthritis, osteoarthritis, multiplesclerosis, asthma, ARDS, psoriasis, vasculitis, ischemia/reperfusioninjury, frostbite, and related diseases.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or controlling diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of Formula Iare indicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.1 milligram to about 100 milligram per kilogram of animalbody weight, preferably given as a single daily dose or in divided dosestwo to six times a day, or in sustained release form. For most largemammals, the total daily dosage is from about 1.0 milligrams to about1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 1 milligram to about 350 milligrams. For aparticularly potent compound, the dosage for an adult human may be aslow as 0.1 mg. The dosage regimen may be adjusted within this range oreven outside of this range to provide the optimal therapeutic response.

Oral administration will usually be carried out using tablets. Examplesof doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg,100 mg, and 250 mg. Other oral forms can also have the same dosages(e.g. capsules).

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I or apharmaceutically acceptable salt as an active ingredient, as well as apharmaceutically acceptable carrier and optionally other therapeuticingredients. The term “pharmaceutically acceptable salts” refers tosalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic bases or acids and organic bases or acids. Apharmaceutical composition may also comprise a prodrug, or apharmaceutically acceptable salt thereof, if a prodrug is administered.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination Therapy

Compounds of Formula I may be used in combination with other drugs thatmay also be useful in the treatment or amelioration of the diseases orconditions for which compounds of Formula I are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of Formula I. When acompound of Formula I is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of Formula I is preferred. However, thecombination therapy also includes therapies in which the compound ofFormula I and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compound ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other PPAR gamma agonists and partial agonists, such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, balaglitazone, netoglitazone, and the like), and PPARgamma agonists and partial agonists that do not have a glitazonestructure;

(b) biguanides such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,

(d) dipeptidyl peptidase IV (DP-IV) inhibitors;

(e) insulin or insulin mimetics;

(f) sulfonylureas such as tolbutamide and glipizide, or relatedmaterials;

(g) α-glucosidase inhibitors (such as acarbose);

(h) agents which improve a patient's lipid profile, such as (i) HMG-CoAreductase inhibitors (lovastatin, simvastatin, rosuvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522and other statins), (ii) bile acid sequestrants (cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARα agonists such as fenofibric acid derivatives (gemfibrozil,clofibrate, fenofibrate and bezafibrate), (v) cholesterol absorptioninhibitors, such as for example ezetimibe, (vi) acyl CoA:cholesterolacyltransferase (ACAT) inhibitors, such as avasimibe, (vii) CETPinhibitors, and (viii) phenolic anti-oxidants, such as probucol;

(i) PPARα/γ dual agonists, such as KRP-297;

(j) PPARδ agonists such as those disclosed in WO97/28149;

(k) antiobesity compounds such as fenfluramine, dexfenfluramine,phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4ragonists, cannabinoid receptor 1 (CB-1) antagonists/inverse agonists,and β₃ adrenergic receptor agonists;

(l) ileal bile acid transporter inhibitors;

(m) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclo-oxygenase 2 selective inhibitors;

(n) glucagon receptor antagonists;

(o) GLP-1,

(p) GIP-1, and

(q) GLP-1 analogs, such as exendins.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula I with two or more active compounds selectedfrom biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPARagonists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesitycompounds.

Biological Assays

A) PPAR Binding Assays

For preparation of recombinant human PPARγ, PPARδ, and PPARα: HumanPPARγ₂, human PPARδ and human PPARα were expressed as gst-fusionproteins in E. coli. The full length human cDNA for PPARγ₂ was subclonedinto the pGEX-2T expression vector (Pharmacia). The full length humancDNAs for PPARδ and PPARα were subcloned into the pGEX-KT expressionvector (Pharmacia). E. coli containing the respective plasmids werepropagated, induced, and harvested by centrifugation. The resuspendedpellet was broken in a French press and debris was removed bycentrifugation at 12,000×g. Recombinant human PPAR receptors werepurified by affinity chromatography on glutathione sepharose. Afterapplication to the column, and one wash, receptor was eluted withglutathione. Glycerol (10%) was added to stabilize the receptor andaliquots were stored at −80° C. For binding to PPARγ, an aliquot ofreceptor was incubated in TEGM (10 mM Tris, pH 7.2, 1 mM EDTA, 10%glycerol, 7 μL/100 mL β-mercaptoethanol, 10 mM Na molybdate, 1 mMdithiothreitol, 5 μg/mL aprotinin, 2 μg/mL leupeptin, 2 μg/mLbenzamidine and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 10 nM[³H₂] AD5075, (21 Ci/mmole),±test compound as described in Berger et al(Novel peroxisome proliferator-activated receptor (PPARγ) and PPARδligands produce distinct biological effects. J. Biol. Chem. (1999), 274:6718-6725. Assays were incubated for ˜16 hr at 4° C. in a final volumeof 150 μL. Unbound ligand was removed by incubation with 100 μLdextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

For binding to PPARδ, an aliquot of receptor was incubated in TEGM (10mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol,10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mLleupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fatdry milk and 2.5 nM [³H₂]L-783483, (17 Ci/mmole),±test compound asdescribed in Berger et al (Novel peroxisome proliferator-activatedreceptory (PPARγ) and PPARδ ligands produce distinct biological effects.1999 J Biol Chem 274: 6718-6725). (L-783483 is3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5]-isoxazoloxy)propylthio)phenylaceticacid, Ex. 20 in WO 97/28137). Assays were incubated for ˜16 hr at 4° C.in a final volume of 150 μL. Unbound ligand was removed by incubationwith 100 μL dextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

For binding to PPARα, an aliquot of receptor was incubated in TEGM (10mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 μL/100 mL β-mercaptoethanol,10 mM Na molybdate, 1 mM dithiothreitol, 5 μg/mL aprotinin, 2 μg/mLleupeptin, 2 μg/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fatdry milk and 5.0 nM [³H₂]L-797773, (34 Ci/mmole),±test compound.(L-797733 is(3-(4-(3-phenyl-7-propyl-6-benz-[4,5]-isoxazoloxy)butyloxy))phenylaceticacid, Ex. 62 in WO 97/28137). Assays were incubated for ˜16 hr at 4° C.in a final volume of 150 μL. Unbound ligand was removed by incubationwith 100 μL dextran/gelatin-coated charcoal, on ice, for ˜10 min. Aftercentrifugation at 3000 rpm for 10 min at 4° C., 50 μL of the supernatantfraction was counted in a Topcount.

B) Gal-4 hPPAR Transactivation Assays

The chimeric receptor expression constructs, pcDNA3-hPPARγ/GAL4,pcDNA3-hPPARδ/GAL4, pcDNA3-hPPARα/GAL4 were prepared by inserting theyeast GAL4 transcription factor DBD adjacent to the ligand bindingdomains (LBDs) of hPPARγ, hPPARδ, hPPARα, respectively. The reporterconstruct, pUAS(5X)-tk-luc was generated by inserting 5 copies of theGAL4 response element upstream of the herpes virus minimal thymidinekinase promoter and the luciferase reporter gene. pCMV-lacZ contains thegalactosidase Z gene under the regulation of the cytomegaloviruspromoter. COS-1 cells were seeded at 12×10³ cells/well in 96 well cellculture plates in high glucose Dulbecco's modified Eagle medium (DMEM)containing 10% charcoal stripped fetal calf serum (Gemini Bio-Products,Calabasas, Calif.), nonessential amino acids, 100 units/ml Penicillin Gand 100 mg/ml Streptomycin sulfate at 37° C. in a humidified atmosphereof 10% CO₂. After 24 h, transfections were performed with Lipofectamine(GIBCO BRL, Gaithersburg, Md.) according to the instructions of themanufacturer. Briefly, transfection mixes for each well contained 0.48μl of Lipofectamine, 0.00075 μg of pcDNA3-PPAR/GAL4 expression vector,0.045 μg of pUAS(5X)-tk-luc reporter vector and 0.0002 μg of pCMV-lacZas an internal control for transactivation efficiency. Cells wereincubated in the transfection mixture for 5 h at 37° C. in an atmosphereof 10% CO₂. The cells were then incubated for ˜48 h in fresh highglucose DMEM containing 5% charcoal stripped fetal calf serum,nonessential amino acids, 100 units/ml Penicillin G and 100 mg/mlStreptomycin sulfate±increasing concentrations of test compound. Sincethe compounds were solubilized in DMSO, control cells were incubatedwith equivalent concentrations of DMSO; final DMSO concentrationswere≦0.1%, a concentration which was shown not to effect transactivationactivity. Cell lysates were produced using Reporter Lysis Buffer(Promega, Madison, Wis.) according to the manufacturer's instructions.Luciferase activity in cell extracts was determined using LuciferaseAssay Buffer (Promega, Madison, Wis.) in an ML3000 luminometer (DynatechLaboratories, Chantilly, Va.). β-galactosidase activity was determinedusing β-D-galactopyranoside (Calbiochem, San Diego, Calif.).

Agonism is determined by comparison of maximal transactivation activitywith a full PPAR agonist, such as rosiglitazone. Generally, if themaximal stimulation of transactivation is less than 50% of the effectobserved with a full agonist, then the compound is designated as apartial agonist. If the maximal stimulation of transactivation isgreater than 50% of the effect observed with a full agonist, then thecompound is designated as a full agonist. The compounds of thisinvention have EC50 values in the range of 1 nM to 3000 nM.

C) In Vivo Studies

Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor,Me.) were housed 5/cage and allowed ad lib. access to ground Purinarodent chow and water. The animals, and their food, were weighed every 2days and were dosed daily by gavage with vehicle (0.5%carboxymethylcellulose)±test compound at the indicated dose. Drugsuspensions were prepared daily. Plasma glucose, and triglycerideconcentrations were determined from blood obtained by tail bleeds at 3-5day intervals during the study period. Glucose, and triglyceride,determinations were performed on a Boehringer Mannheim Hitachi 911automatic analyzer (Boehringer Mannheim, Indianapolis, Ind.) usingheparinized plasma diluted 1:6 (v/v) with normal saline. Lean animalswere age-matched heterozygous mice maintained in the same manner.

EXAMPLES

The following Examples are provided to illustrate the invention and arenot to be construed as limiting the invention in any manner. The scopeof the invention is defined by the appended claims.

Specific compounds that were made are presented in Tables 1-4. The namesare provided in Tables 1A-4A. The tables are provided immediately afterthe examples below. The compounds in the tables are grouped according tosimilar structural features, as follows. Representative syntheses ofsome of the compounds are presented below. The remaining compounds weremade using similar synthetic strategies and methods and readilyavailable reagents and starting materials. Such syntheses are readilyapparent to practitioners in the field of synthetic organic chemistry.

Table 1: R³ is Phenoxy or Thiophenoxy;

Table 2: R³ is Benzisoxazole;

Table 3: R³ is Benzoyl; and

Table 4: R³ is Phenyl.

All compounds in Tables 1-4 were analyzed by tandem high pressure liquidchromatography—mass spectrometry (LC-MS) and/or proton NMR. LC-MSsamples were analyzed using an Agilent 1100 Series high pressure liquidchromatograph coupled to a Waters Micromass ZQ mass spectrometer. Thecolumn used was a Waters XTerra and compounds were eluted using agradient elution program (10% B to 100% B in 4.5 min) with a flow rateof 2.5 ml/min. Solvent A: water containing 0.06% trifluoroacetic acid.Solvent B: acetonitrile containing 0.05% trifluoroacetic acid. Retentiontimes are given in minutes.

Syntheses of Compounds in which R³ is Benzoyl (Table 3)

Example 1

(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid

Step 1: 1-(3-methoxy)phenyl-2-methyl-6-trifluoromethoxyindole (1):

2-Methyl-6-trifluoromethoxyindole (645 mg, 3.0 mmole), 3-bromoanisole(0.456 ml, 3.6 mmole), sodium t-butoxide (404 mg, 4.2 mmole),trisdibenzylidine dipalladium (206 mg, 0.225 mmole) and2-di-t-butylphosphinobiphenyl (201 mg, 0.675 mmole) were stirred intoluene at 80° C. and monitored by TLC (3/1 hexanes/methylene chloride)or reversed phase HPLC until complete. The reaction mixture was thencooled, filtered over celite, and the filtrate evaporated to give acrude isolate, which was purified by silica gel chromatography to givethe title compound.

¹H NMR (500 MHz, CDCl₃): δ 7.53 (d, Ph, 1H), 7.48 (t, Ph, 1H), 7.05 (dd,Ph, 1H), 7.02 (m, Ph, 2H), 6.95 (dd, ph, 1H), 6.89 (t, Ph, 1H), 6.42 (s,Ph, 1H), 3.88 (s, OCH₃, 3H), 2.33 (s, 2-CH₃, 3H).

Step 2: 1-(3-hydroxy)phenyl-2-methyl-6-trifluoromethoxyindole (2):

460 mg (1.43 mmole) of (1) was dissolved in 7 mL of dichloromethane at0° C. Boron tribromide (1.0 N, 2.86 mL) in dichloromethane was added,the cooling bath was removed and the reaction was stirred at roomtemperature overnight. The reaction was then quenched with ice for 30minutes and partitioned. The organic was washed with water and driedover sodium sulfate. After filtering the drying agent, the filtrate wasevaporated and the residue chromatographed over silica gel to give thetitle compound.

¹H NMR (500 MHz, CDCl₃): δ 7.51 (d, Ph, 1H), 7.42 (t, Ph, 1H), 7.00 (d,Ph, 1H), 6.98 (s, Ph, 1H), 6.95 (dd, ph, 1H), 6.92 (dd, Ph, 1H), 6.82(t, Ph, 1H), 6.39 (s, Ph, 1H), 5.03 (s, OH, 1H), 2.31 (s, 2-CH₃, 3H).

Step 3:1-(3-hydroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-6-trifluoromethoxyindole(3):

242 mg (0.788 mmole) of (2) was dissolved in methylene chloride (4 ml)and cooled to −20° C. A solution of diethylaluminum chloride in toluene(1.8M, 1.23 ml) was added slowly (over 1-2 minutes) and stirred for 5-15minutes. Then added a solution of 4-methoxybenzoyl chloride (377 mg,2.21 mmole) in methylene chloride (1 mL) and allowed to stir overnightwhile slowly reaching room temperature. Added pH 7.0 buffer dropwiseuntil gas evolution ceased, then partitioned. The aqueous layer wasextracted twice more with methylene chloride, and then the combinedorganic layers were washed twice with saturated NaCl solution, driedover sodium sulfate, filtered and evaporated. The crude isolate was thendissolved in methanol (5 mL) and sodium hydroxide solution (1.0 M, 1.6mL) was added. Monitored by TLC for disappearance of di-acyl indole,then neutralized with HCl (1.0 M, 1.6 mL). The reaction mixture was thendiluted with water and extracted with ethyl acetate. The ethyl acetatelayer was dried over sodium sulfate, filtered, evaporated and theresidue chromatographed by silica gel chromatography to give the titlecompound.

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, Ph, 2H), 7.46 (d, Ph, 1H), 7.42 (t,Ph, 1H), 7.06 (dd, Ph, 1H), 6.98 (m, Ph, 3H), 6.95 (s, ph, 1H), 6.92(dd, Ph, 1H), 6.86 (t, Ph, 1H), 6.38 (s, OH, 1H), 3.91 (s, OCH₃, 3H),2.35 (s, 2-CH₃, 3H).

Step 4:(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid ethyl ester (4):

45.9 mg (0.100 mmole) of (3) was dissolved in tetrahydrofuran (0.5 mL)and cooled to 0° C. Triphenylphosphine (34 mg, 0.130 mmole) and(S)-ethyl lactate (14.7 μL, 0.130 mmole) were then added, followed bydiethylazodicarboxylate (20.5 μL, 0.13 mmole). The reaction was stirredovernight and then directly chromatographed on silica gel to give thetitle compound.

¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, Ph, 2H), 7.53 (t, Ph, 1H), 7.47 (d,Ph, 1H), 7.090 (d, Ph, 1H), 7.01 (m, Ph, 4H), 6.95 (m, Ph, 1H), 6.89 (s,Ph, 1H), 4.83 (br m, OCH(CH₃)CO₂Et, 1H), 3.93 (s, OCH₃, 3H), 4.25 (q,OCH(CH₃)CO₂ CH ₂CH₃, 2H), 2.40 (s, 2-CH₃, 3H), 1.70 (d, OCH(CH ₃)CO₂Et,3H), 1.28 (q, OCH(CH₃)CO₂CH₂ CH ₃, 3H).

Step 5:(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid (5):

56 mg of (4) was dissolved in ethanol (1 mL) and aqueous sodiumhydroxide (1.0 M, 0.200 mL) and stirred until hydrolysis was complete.The reaction was diluted with water, acidified with dilute aqueous HCland extracted with ethyl acetate. The organic was dried over sodiumsulfate, filtered and evaporated to give the title compound.

¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, Ph, 2H), 7.54 (t, Ph, 1H), 7.45 (brs, Ph, 1H), 7.11 (br s, Ph, 1H), 7.02 (m, Ph, 4H), 6.95 (m, Ph, 2H),4.88 (br m, OCH(CH₃)CO₂H, 1H), 3.93 (s, OCH₃, 3H), 2.41 (s, 2-CH₃, 3H),1.74 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=3.88 min, m/e 514 (M+1)

Example 2

(2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid

This compound was made using a synthetic method analogous to Example 1and using readily available reagents and starting materials. Such asynthesis can be readily carried out by a practitioner in the field ofsynthetic organic chemistry.

¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, Ph, 2H), 7.54 (t, Ph, 1H), 7.45 (brs, Ph, 1H), 7.11 (br s, Ph, 1H), 7.02 (m, Ph, 4H), 6.95 (m, Ph, 2H),4.88 (br m, OCH(CH₃)CO₂H, 1H), 3.93 (s, OCH₃, 3H), 2.41 (s, 2-CH₃, 3H),1.74 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=3.88 min, m/e 514 (M+1)

Example 3

Scheme for Example 3:

Example 3

(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

Step 1: 1-(3-methoxy)phenyl-2-methyl-6-trifluoromethoxyindole (1):

2-Methyl-6-trifluoromethoxyindole (645 mg, 3.0 mmole), 3-bromoanisole(0.456 ml, 3.6 mmole), sodium t-butoxide (404 mg, 4.2 mmole),trisdibenzylidine dipalladium (206 mg, 0.225 mmole) and2-di-t-butylphosphinobiphenyl (201 mg, 0.675 mmole) were stirred intoluene at 80° C. and monitored by TLC (3/1 hexanes/methylene chloride)or reversed phase HPLC until complete. The reaction mixture was thencooled, filtered over celite, and the filtrate evaporated to give acrude isolate, which was purified by silica gel chromatography to givethe title compound.

¹H NMR (500 MHz, CDCl₃): δ 7.53 (d, Ph, 1H), 7.48 (t, Ph, 1H), 7.05 (dd,Ph, 1H), 7.02 (m, Ph, 2H), 6.95 (dd, ph, 1H), 6.89 (t, Ph, 1H), 6.42 (s,Ph, 1H), 3.88 (s, OCH₃, 3H), 2.33 (s, 2-CH₃, 3H).

Step 2: 1-(3-hydroxy)phenyl-2-methyl-6-trifluoromethoxyindole (2):

460 mg (1.43 mmole) of (1) was dissolved in 7 mL of dichloromethane at0° C. Boron tribromide (1.0 N, 2.86 mL) in dichloromethane was added,the cooling bath was removed and the reaction was stirred at roomtemperature overnight. The reaction was then quenched with ice for 30minutes and partitioned. The organic was washed with water and driedover sodium sulfate. After filtering the drying agent, the filtrate wasevaporated and the residue chromatographed over silica gel to give thetitle compound.

¹H NMR (500 MHz, CDCl₃): δ 7.51 (d, Ph, 1H), 7.42 (t, Ph, 1H), 7.00 (d,Ph, 1H), 6.98 (s, Ph, 1H), 6.95 (dd, ph, 1H), 6.92 (dd, Ph, 1H), 6.82(t, Ph, 1H), 6.39 (s, Ph, 1H), 5.03 (s, OH, 1H), 2.31 (s, 2-CH₃, 3H).

Step 3:1-(3-hydroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-6-trifluoromethoxyindole(3):

242 mg (0.788 mmole) of (2) was dissolved in methylene chloride (4 ml)and cooled to −20° C. A solution of diethylaluminum chloride in toluene(1.8M, 1.23 ml) was added slowly (over 1-2 minutes) and stirred for 5-15minutes. Then added a solution of 4-methoxybenzoyl chloride (377 mg,2.21 mmole) in methylene chloride (1 mL) and allowed to stir overnightwhile slowly reaching room temperature. Added pH 7.0 buffer dropwiseuntil gas evolution ceased, then partitioned. The aqueous layer wasextracted twice more with methylene chloride, and then the combinedorganic layers were washed twice with saturated NaCl solution, driedover sodium sulfate, filtered and evaporated. The crude isolate was thendissolved in methanol (5 mL) and sodium hydroxide solution (1.0 M, 1.6mL) was added. Monitored by TLC for disappearance of di-acyl indole,then neutralized with HCl (1.0 M, 1.6 mL). The reaction mixture was thendiluted with water and extracted with ethyl acetate. The ethyl acetatelayer was dried over sodium sulfate, filtered, evaporated and theresidue chromatographed by silica gel chromatography to give the titlecompound.

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, Ph, 2H), 7.46 (d, Ph, 1H), 7.42 (t,Ph, 1H), 7.06 (dd, Ph, 1H), 6.98 (m, Ph, 3H), 6.95 (s, ph, 1H), 6.92(dd, Ph, 1H), 6.86 (t, Ph, 1H), 6.38 (s, OH, 1H), 3.91 (s, OCH_(3, 3)H),2.35 (s, 2-CH₃, 3H).

Step 4:(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid t-butyl ester (4):

110 mg (0.25 mmole) of (3) was dissolved in tetrahydrofuran (1.25 mL)and cooled to 0° C. Triphenylphosphine (78.5 mg, 0.30 mmole) andt-butyl-(S)-2-hydroxybutyrate (Sigma-Aldrich, 48 mg, 0.30 mmole) werethen added, followed by diisopropylazodicarboxylate (59 μL, 0.30 mmole).The reaction was stirred overnight and then directly chromatographed onsilica gel to give 100 mg of the title compound. Chiral purity wasassessed by chromatographic comparison on a Chiralcel AD column(heptane/isopropanol as eluents) with the opposite enantiomer (preparedas above using t-butyl-(R)-2-hydroxybutyrate in place oft-butyl-(S)-2-hydroxybutyrate).

Chiral LC: 10% isopropanol/heptane, 0.5 ml/min, λ=220 nm, Chiralcel ADcolumn (4.6×250 mm, 10 μ):

t_(R) (4): 12.68 min (99.7%), 14.16 (0.3%). t_(R) of (S) enantiomer(t-butyl ester of example 2): 12.68 min (2.2%), 14.18 min (97.8%).

¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, Ph, 2H), 7.51 (t, Ph, 1H), 7.47 (d,Ph, 1H), 7.08 (d, Ph, 1H), 7.00 (m, Ph, 4H), 6.93 (m, Ph, 1H), 6.89 (brt, Ph, 1H), 4.52 (t, OCH(CH₂CH₃)CO₂t-Bu, 1H), 3.93 (s, OCH₃, 3H), 2.39(s, 2-CH₃, 3H), 2.03 (m, OCH(CH ₂CH₃)CO₂t-Bu, 2H), 1.45 (s,OCH(CH₂CH₃)CO₂t-Bu, 9H), 1.13 (t, OCH(CH₂ CH ₃)CO₂t-Bu, 3H),

Step 5:(2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid (5):

17 mg (0.03 mole) of (4) was dissolved in dichloromethane (1 mL) andtrifluoroacetic acid (0.5 mL, large excess) was added. The reaction wasstirred until complete (monitored by TLC). Evaporated solvent andtrifluoroacetic acid, reconstituted in dichloromethane, washedsuccessively with pH 7.0 phosphate buffer (Fisher Scientific) and sodiumchloride solution. The dichloromethane was dried over sodium sulfate,filtered and evaporated. The compound can then be purified by either ODSor silica gel column (0.5% to 1% acetic acid/ethyl acetate/hexanesneeded for silica gel purification).

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, Ph, 2H), 7.62 (t, Ph, 1H), 7.61 (brm, Ph, 1H), 7.22 (dd, Ph, 1H), 7.17 (br m, Ph, 2H), 7.11 (m, Ph, 1H),7.08 (m, Ph, 2H), 7.04-6.96 (br d, pH, 1H), 4.90 (m, OCH(CH₂CH₃)CO₂H,1H), 3.93 (s, OCH₃, 3H), 2.33 (br s, 2-CH₃, 3H), 2.06 (m, OCH(CH₂CH₃)CO₂H, 2H), 1.11 (t, OCH(CH₂ CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=3.74 min, m/e 528 (M+1)

Examples 4-27

The following compounds were prepared in a similar manner to theexamples above using analogous synthetic methods and strategies andreadily available starting materials and reagents. Such methods andstarting materials are readily apparent to a practitioner in the fieldof synthetic organic chemistry.

Example 4

(2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, Ph, 2H), 7.62 (t, Ph, 1H), 7.61 (brm, Ph, 1H), 7.22 (dd, Ph, 1H), 7.17 (br m, Ph, 2H), 7.11 (m, Ph, 1H),7.08 (m, Ph, 2H), 7.04-6.96 (br d, pH, 1H), 4.90 (m, OCH(CH₂CH₃)CO₂H,1H), 3.93 (s, OCH₃, 3H), 2.33 (br s, 2-CH₃, 3H), 2.06 (m, OCH(CH₂CH₃)CO₂H, 2H), 1.11 (t, OCH(CH₂ CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=3.74 min, m/e 528 (M+1).

Example 5

2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.88 (br, Ph, 2H), 7.53 (t, Ph, 1H), 7.44 (d,Ph, 1H), 7.14 (d, Ph, 1H), 7.08 (d, Ph, 1H), 7.01 (m, Ph, 3H), 6.95 (d,Ph, 2H), 3.93 (s, OCH₃, 3H), 2.43 (br s, 2-CH₃, 3H), 1.70 (s,OC(CH₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=3.96 min, m/e 528 (M+1)

Example 6

(2R)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.55 (t, Ph, 1H), 7.49 (d,Ph, 2H), 7.37 (br m, Ph, 1H), 7.12 (br m, Ph, 1H), 7.03 (br m, Ph, 2H),6.93 (br m, Ph, 2H), 4.88 (br m, OCH(CH₃)CO₂H, 1H), 3.93 (s, OCH₃, 3H),2.41 (s, 2-CH₃, 3H), 1.74 (d, OCH(CH ₂H)CO₂H, 3H).

RP LC/MS: t_(R)=4.18 min, m/e 518 (M+1)

Example 7

(2S)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.55 (t, Ph, 1H), 7.49 (d,Ph, 2H), 7.37 (br m, Ph, 1H), 7.12 (br m, Ph, 1H), 7.03 (br m, Ph, 2H),6.93 (br m, Ph, 2H), 4.88 (br m, OCH(CH₃)CO₂H, 1H), 3.93 (s, OCH₃, 3H),2.41 (s, 2-CH₃, 3H), 1.74 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.18 min, m/e 518 (M+1)

Example 8

(2R)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.55 (t, Ph, 1H), 7.50 (d,Ph, 2H), 7.37 (br m, Ph, 1H), 7.13 (br m, Ph, 1H), 7.03 (br m, Ph, 2H),6.95 (br m, Ph, 2H), 4.72 (br m, OCH(CH₂CH₃)CO₂H, 1H), 2.42 (s, 2-CH₃,3H), 2.11 (m, OCH(CH ₂CH₃)CO₂H, 2H), 1.17 (t, OCH(CH₂ CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.01 min, m/e 532 (M+1)

Example 9

(2S)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.55 (t, Ph, 1H), 7.50 (d,Ph, 2H), 7.37 (br m, Ph, 1H), 7.13 (br m, Ph, 1H), 7.03 (br m, Ph, 2H),6.95 (br m, Ph, 2H), 4.72 (br m, OCH(CH₂CH₃)CO₂H, 1H), 2.42 (s, 2-CH₃,3H), 2.11 (m, OCH(CH ₂CH₃)CO₂H, 2H), 1.17 (t, OCH(CH₂ CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.01 min, m/e 532 (M+1)

Example 10

2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (br, Ph, 2H), 7.53 (t, Ph, 1H), 7.44 (d,Ph, 2H), 7.37 (d, Ph, 1H), 7.15 (dd, Ph, 1H), 7.07 (dd, Ph, 1H), 7.03(d, Ph, 1H), 6.95 (t, Ph, 1H), 6.93 (s, Ph, 1H), 2.42 (br s, 2-CH₃, 3H),1.71 (s, OC(CH₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=4.30 min, m/e 532 (M+1)

Example 11

(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl-]5-fluorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (brm, Ph, 1H), 7.04 (d, Ph, 1H), 6.97 (br m, Ph, 1H), 6.86 (d, Ph, 1H),6.78 (d, Ph, 1H), 6.72 (m, Ph, 1H), 4.85 (q, OCH(CH₃)CO₂H, 1H), 2.43 (s,2-CH₃, 3H), 1.75 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.21 min, m/e 536 (M+1)

Example 12

(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (brm, Ph, 1H), 7.04 (d, Ph, 1H), 6.97 (br m, Ph, 1H), 6.86 (d, Ph, 1H),6.78 (d, Ph, 1H), 6.72 (m, Ph, 1H), 4.85 (q, OCH(CH₃)CO₂H, 1H), 2.43 (s,2-CH₃, 3H), 1.75 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.21 min, m/e 536 (M+1)

Example 13

(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (brm, Ph, 1H), 7.04 (d, Ph, 1H), 6.97 (br m, Ph, 1H), 6.86 (d, Ph, 1H),6.78 (d, Ph, 1H), 6.73 (m, Ph, 1H), 4.68 (q, OCH(CH₂CH₃)CO₂H, 1H), 2.43(s, 2-CH₃, 3H), 2.11 (m, OCH(CH ₂CH₃)CO₂H, 2H), 1.16 (t, OCH(CH₂ CH₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.05 min, m/e 550 (M+1)

Example 14

(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (brm, Ph, 1H), 7.04 (d, Ph, 1H), 6.97 (br m, Ph, 1H), 6.86 (d, Ph, 1H),6.78 (d, Ph, 1H), 6.73 (m, Ph, 1H), 4.68 (q, OCH(CH₂CH₃)CO₂H, 1H), 2.43(s, 2-CH₃, 3H), 2.11 (m, OCH(CH ₂CH₃)CO₂H, 2H), 1.16 (t, OCH(CH₂ CH₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.05 min, m/e 550 (M+1)

Example 15

2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}-2-methylpropanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.35 (d,Ph, 1H), 7.03 (d, Ph, 1H), 6.94 (s, Ph, 1H), 6.87 (dt, Ph, 1H), 6.80(dt, Ph, 1H), 6.71 (m, Ph, 1H), 2.42 (s, 2-CH₃, 3H), 1.71 (s, OC(CH₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=4.41 min, m/e 550 (M+1)

Example 16

(2R)-2-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.86 (d, Ph, 2H), 7.44 (br m, Ph, 1H), 7.03(d, Ph, 1H), 7.00 (d, Ph, 2H), 6.97 (br m, Ph, 1H), 6.85 (d, Ph, 1H),6.79 (d, Ph, 1H), 6.73 (m, Ph, 1H), 4.86 (q, OCH(CH₃)CO₂H, 1H), 3.93 (s,OCH₃, 3H), 2.42 (s, 2-CH₃, 3H), 1.75 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=3.64 min, m/e 532 (M+1)

Example 17

(2R)-2-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.86 (d, Ph, 2H), 7.44 (br m, Ph, 1H), 7.03(d, Ph, 1H), 7.00 (d, Ph, 2H), 6.97 (br m, Ph, 1H), 6.86 (d, Ph, 1H),6.78 (d, Ph, 1H), 6.73 (m, Ph, 1H), 4.67 (q, OCH(CH₂CH₃)CO₂H, 1H), 2.42(s, 2-CH₃, 3H), 2.11 (m, OCH(CH ₂CH₃)CO₂H, 2H), 1.16 (t, OCH(CH₂ CH₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.13 min, m/e 546 (M+1)

Example 18

(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-fluorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.78 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (dd,Ph, 1H), 7.31 (m, Ph, 1H), 7.02 (br m, Ph, 2H), 6.96 (br d, Ph, 1H),6.89 (d, Ph, 1H), 4.88 (m, OCH(CH₃)CO₂H, 1H), 2.40 (s, 2-CH₃, 3H), 1.76(d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.15 min, m/e 536 (M+1)

Example 19

(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-fluorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.78 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (dd,Ph, 1H), 7.31 (m, Ph, 1H), 7.02 (br m, Ph, 2H), 6.96 (br d, Ph, 1H),6.89 (d, Ph, 1H), 4.88 (m, OCH(CH₃)CO₂H, 1H), 2.40 (s, 2-CH₃, 3H), 1.76(d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.15 min, m/e 536 (M+1)

Example 20

(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-fluorophenoxy}-2-methylpropanoic acid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.49 (d, Ph, 2H), 7.36 (dd,Ph, 1H), 7.34 (m, Ph, 1H), 7.12 (m, Ph, 2H), 7.03 (br d, Ph, 1H), 6.89(d, Ph, 1H), 2.42 (s, 2-CH₃, 3H), 1.70 (s, OC(CH ₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=4.33 min, m/e 550 (M+1)

Example 21

2-({6-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridin-2-yl}oxy)-2-methylpropanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.67 (d, Ph, 2H), 7.51 (m, Ph, 1H), 7.11 (d,Ph, 1H), 7.00 (s, Ph, 1H), 6.82 (m, Ph, 5H), 3.83 (s, OCH₃, 3H), 2.42(s, 2-CH₃, 3H), 1.70 (s, OC(CH ₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=3.91 min, m/e 529 (M+1)

Example 22

2-({6-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridin-2-yl}oxy)-2-methylpropanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.90 (t, Ph, 1H), 7.79 (d, Ph, 2H), 7.49 (d,Ph, 2H), 7.41 (d, Ph, 1H), 7.05 (m, Ph, 3H), 6.98 (d, Ph, 1H), 2.44 (s,2-CH₃, 3H), 1.65 (s, OC(CH ₃)₂CO₂H, 6H).

RP LC/MS: t_(R)=4.17 min, m/e 533 (M+1)

Example 23

(2S)-2-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-chlorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.85 (d, Ph, 2H), 7.65 (d, Ph, 1H), 7.31 (m,Ph, 1H), 7.03-6.90 (br m, Ph, 6H), 4.85 (m, OCH(CH₃)CO₂H, 1H), 3.93 (s,OCH₃, 3H), 2.41 (s, 2-CH₃, 3H), 1.78 (d, OCH(CH ₃)CO₂H, 3H).

Example 24

(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-chlorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.78 (d, Ph, 2H), 7.65 (d, Ph, 1H), 7.49 (d,Ph, 2H), 7.34 (m, Ph, 1H), 7.02-6.86 (br m, Ph, 4H), 4.86 (br m,OCH(CH₃)CO₂H, 1H), 2.41 (s, 2-CH₃, 3H), 1.79 (d, OCH(CH ₃)CO₂H, 3H).

RP LC/MS: t_(R)=4.37 min, m/e 551 (M+1)

Example 25

(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-4-chlorophenoxy}propanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.78 (d, Ph, 2H), 7.65 (d, Ph, 1H), 7.49 (d,Ph, 2H), 7.34 (m, Ph, 1H), 7.02-6.86 (br m, Ph, 4H), 4.86 (br m,OCH(CH₃)CO₂H, 1H), 2.41 (s, 2-CH₃, 3H), 1.79 (d, OCH(CH ₃)CO₂H, 3H).

Example 26

2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.80 (d, Ph, 2H), 7.55 (t, Ph, 1H), 7.50 (d,Ph, 2H), 7.37 (m, Ph, 1H), 7.16-6.85 (br m, Ph, 5H), 4.60 (br s,OCH(CH₂CH₃)CO₂H, 1H), 2.41 (s, 2-CH₃, 3H), 2.11 (m, OCH(CH₂ CH₃)CO₂H,2H), 1.16 (t, OCH(CH₂ CH₃ )CO₂H, 3H).

Example 27

2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}pentanoicacid

¹H NMR (500 MHz, CDCl₃): δ 7.79 (d, Ph, 2H), 7.54 (t, Ph, 1H), 7.49 (d,Ph, 2H), 7.38-7.34 (m, Ph, 1H), 7.12-6.89 (br m, Ph, 5H), 4.74 (br s,OCH(CH₂CH₂CH₃)CO₂H, 1H), 2.41 (s, 2-CH₃, 3H), 2.04 (m, OCH(CH₂CH₂CH₃)CO₂H, 2H), 1.63 (m, OCH(CH₂ CH₂ CH₃)CO₂H, 2H), 1.03 (t,OCH(CH₂CH₂ CH₃ )CO₂H, 3H).

Scheme for the Synthesis of Example 28

Example 28

Ketone 2:

A suspension of chloroacetone (6.00 gr, 65 mmol, the chloroacetone wasfiltered through basic alumina prior to use), phenol 1 (10.00 gr, 65mmole) and potassium carbonate (8.96 gr, 65 mmol) was stirred in DMF atroom temperature under nitrogen atmosphere for 1 h. After this time thereaction was diluted with ethyl acetate/H2O and the layers wereseparated. The aqueous layer was acidified with 1N HCl and extractedwith ethyl acetate (3×). The organic layer was then washed with water(2×), and brine (1×), dried with sodium sulfate, filtered and evaporatedto give a pink solid: ¹H-NMR (CDCl₃, 500 MHz) δ 8.14 (t, 1H), 7.53 (t,1H), 7.35 (d, 1H), 7.27 (d, 1H), 3.78 (s, 2H), 2.35 (s, 3H).

Indole 3:

Ketone 2 (1.84 gr, 8.75 mmol) and 4-trifluoromethoxy phenylhydrazinehydrochloride (2.00 gr, 4.76 mmol) were stirred at 100° C. in aceticacid (40 ml, 0.22M) for 1 hour under nitrogen atmosphere to give a 1:2mixture of 4- and 6-trifluoromethoxy indoles (desired 6-substitutedindole is slightly less polar by TLC). The reaction was cooled to roomtemperature, the acetic acid was removed under reduced pressure and theresidue was diluted with ethyl acetate and washed with water (1×) andbrine (1×). The organic layer was dried with sodium sulfate, filteredand evaporated to afford 3 as a yellow oil after column chromatography(hexanes/ethyl acetate/1% acetic acid, 6:1); ¹H-NMR (CDCl₃, 500 MHz) δ8.43 (br s, 1H), 8.16 (dd, 1H), 7.46 (d, 1H), 7.23 (t, 1H), 7.14 (t,1H), 7.03 (d, 1H), 6.74 (d, 1H), 2.54 (s, 3H).

3-H Indole 4:

A solution of indole 3 (0.29 gr, 0.78 mmol) and thiosalicylic acid (0.12gr, 0.78 mmol) in trifluoroacetic acid (3 mL, 0.26M) was heated to 50°C. under nitrogen atmosphere for 2 hr. After this time the reaction wascooled to room temperature, diluted with ethyl acetate and washed with1N NaOH (2×), and brine (1×). The organic layer was dried with sodiumsulfate, filtered and evaporated to afford a brown solid: ¹H-NMR (CDCl₃,500 MHz) δ 8.01 (br s, 1H), 7.49 (d, 1H), 7.17 (s, 1H), 6.99 (d, 1H),6.26 (s, 1H), 2.46 (s, 3H).

3-Acylindole 5:

Zinc chloride (0.23 gr, 1.66 mmol) and ethyl magnesium bromide (0.29 mlof a 3M solution in ether, 0.87 mmol) were added to a solution of indole4 (0.16 gr, 0.74 mmol) in CH₂Cl₂. The resulting mixture was stirred atroom temperature under a nitrogen atmosphere for 1 hr. 4-Chlorobenzoylchloride (0.21 gr, 1.18 mmol) was then added and stirring was continuedfor 1 hr. Finally, aluminum chloride (0.053 gr, 0.39 mmol) was added andthe reaction mixture was stirred for 3 hr. After this time, the reactionwas quenched with NH₄Cl(aq), diluted with CH₂Cl₂, washed with 1N NaOH(1×) and brine (3×). The organic layer was dried with sodium sulfate,filtered and evaporated to afford a light yellow oil after columnchromatography (hexanes/ethyl acetate, 4:1); ¹H-NMR (CDCl₃, 500 MHz) δ8.54 (br s, 1H), 7.73 (d, 2H), 7.48 (d, 2H), 7.40 (d, 1H), 7.24 (s, 1H),7.02 (d, 1H), 2.60 (s, 3H).

N-benzyl Indole 6:

Sodium hydride (14 mg, 0.35 mmol, 60% dispersion in mineral oil) wasadded to a solution of indole 5 (111 mg, 0.32 mmol) in DMT (3.0 ml,0.1M). The resulting mixture was stirred at room temperature undernitrogen for 10 min, then bromide 10 (110 mg, 0.35 mmol) was added.Stirring was continued at room temperature for 2 hr. The reactionmixture was then diluted with ethyl acetate, washed with water (2×) andbrine (1×), dried with sodium sulfate, filtered, and evaporated to givea yellow oil after column chromatography (4:1 hexanes/ethyl acetate).¹H-NMR (CDCl₃, 500 MHz) δ 7.76 (d, 2H), 7.48 (d, 2H), 7.37 (d, 1H), 7.26(dd, 1H), 7.14 (s, 1H), 7.02 (d, 1H), 6.79 (dd, 1H), 6.65 (d, 1H), 6.60(s, 1H), 5.34 (s, 2H), 4.72 (q, 1H), 3.89 (m, 2H), 2.55 (s, 3H), 1.88(m, 1H), 1.62 (d, 3H), 0.85 (d, 6H).

Acid 7:

N-Benzyl indole 6 (121 mg, 0.206 mmol) and aqueous sodium hydroxide(0.50 mL, 5.0M) were stirred in tetrahydrofuran, methanol, and water(2.5 ml, 3:1:1) at room temperature for 7 hr. After this time, thereaction concentrated by rotary evaporation and purified by reversephase HPLC to give acid 7 as a white solid. ¹H-NMR (CDCl₃, 500 MHz) δ7.76 (d, 2H), 7.48 (d, 2H), 7.34 (d, 1H), 7.26 (d, 1H), 7.16 (s, 1H),7.02 (d, 1H), 6.82 (dd, 1H), 6.72 (d, 1H), 6.44 (s, 1H), 5.36 (dd, 2H),4.64 (q, 1H), 2.51 (s, 3H), 1.62 (d, 3H).

Phenol 9:

3-Methoxybenzyl bromide (3.0 gr, 15 mmol) was dissolved in CH₂Cl₂ andcooled to 0° C. A 1M solution of boron tribromide in CH₂Cl₂ (17.9 ml,17.9 mmol) was then added dropwise. After 30 min, the ice bath wasremoved and stirring was continued for an additional 30 min. The rxn wasthen quenched with ice and diluted with CH₂Cl₂, H2O. The layers wereseparated and the organic layer was washed with H2O (2×) and brine (1×),dried with sodium sulfate, filtered, and evaporated to give phenol 9 asa white solid. ¹H-NMR (CDCl₃, 500 MHz) δ 7.25 (t, 1H), 6.99 (d, 1H),6.90 (s, 1H), 6.80 (d, 1H), 4.81 (br s, 1H), 4.45 (s, 2H).

Bromide 10:

R-Isobutyl lactate (1.02 gr, 6.95 mmol) was dissolved in CH₂Cl₂ andcooled to 0° C. Triphenylphosphine (1.83 gr, 6.95 mmol) was then addedfollowed by dropwise addition of diethylazodicarboxylate (1.21 gr, 6.95mmol). Finally, phenol 9 was added. After addition, the ice bath wasremoved and stirring was continued for 30 min. The reaction was dilutedwith CH₂Cl₂, washed with H₂O (2×) and brine (1×), dried with sodiumsulfate, filtered and evaporated to give a colorless oil (1.02 gr, 60%)after chromatography (hexanes/ethyl acetate, 8:1). ¹H-NMR (CDCl₃, 500MHz) δ 7.26 (dd, 1H), 7.01 (d, 1H), 6.94 (dd, 1H), 6.83 (dd, 1H), 4.81(q, 1H), 4.46 (s, 2H), 3.23-4.01 (m, 2H), 1.95 (m, 1H), 1.65 (d, 3H),0.90 (dd, 6H).

Scheme for the Synthesis of Example 29

Example 29

Ethyl 2-(3-formyl)phenoxybutyrate:

To a solution of 3-hydroxybenzaldehyde (26.8 g, 219.6 mmol) in DMF (250ml) at 0 to 10° C., was added Cs₂CO₃ (142 g, 439 mmol) and ethyl2-bromobutyrate (32.4 ml, 219.6 mmol). The reaction mixture was firststirred for at 0 to 10° C. for 2 hours, then at room temperatureovernight. The mixture was diluted with water (400 ml), and extractedwith diethyl ether (2×150 ml). The ether extract was washed with water(2×100 ml) and brine (100 ml), and dried over anhydrous MgSO₄, andconcentrated under vacuum to dryness to obtain the product as a clearoil. ¹H NMR (CDCl₃, 500 MHz) δ 9.97 (s, 1H), 7.51 (m, 2H), 7.36 (s, 1H),7.21 (dd, 1H), 4.66 (t, 1H), 4.21 (q, 2H), 2.06 (m, 2H), 1.28 (t, 3H),1.12 (t, 3H).

Ethyl 2-(3-hydroxymethyl)phenoxybutyrate

Sodium borohydride (NaBH₄, 7.4 g, 194 mmol) was added in proportions toa solution of ethyl 2-(3-formyl)phenoxybutyrate (46 g, 194 mmol) inethanol (500 ml) at 0° C. The reaction mixture was stirred in an icebath for 1 hour. Water was added slowly to destroy excess NaBH. Themixture was then diluted with 300 ml of water and extracted with diethylether (2×200 ml). The ether extract was washed with water (2×100 ml) andbrine (100 ml), and dried over anhydrous MgSO₄, and concentrated undervacuum to dryness to obtain the product as a clear oil. ¹H NMR (CDCl₃,500 MHz) 7.27 (dd, 1H), 6.97 (d, 1H), 6.93 (s, 1H), 6.81 (d, 1H), 4.65(s, 2H), 4.58 (t, 1H), 4.22 (q, 2H), 2.01 (m, 2H), 1.28 (t, 3H), 1.11(t, 3H).

Ethyl 2-(3-bromomethyl)phenoxybutyrate

To a solution of ethyl 2-(3-hydroxymethyl)phenoxybutyrate (41 g, 172.2mmol) in dichloromethane (400 ml) at 0° C., was added carbontetrabromide (CBr₄, 86 g, 260 mmol) and triphenylphosphine (Ph₃P, 68 g,260 mmol). The reaction mixture was stirred at 0° C. for 2 hours, thenwashed with saturated sodium bicarbonate (NaHCO₃, 200 ml) and brine (200ml) and concentrated under vacuum to a small volume. The residue waschromatographed on silica gel with hexane/ethyl acetate (9:1) as thesolvent system to obtain the product as a colorless oil. ¹H NMR (CDCl₃,500 MHz) 7.26 (t, 1H), 7.01 (d, 1H), 6.95 (s, 1H), 6.82 (d, 1H), 4.58(m, 1H), 4.46 (s, 2H), 4.25 (q, 2H), 2.01 (m, 2H), 1.28 (t, 3H), 1.11(t, 3H).

Preparation of Optically Active Ethyl 2-(3-bromomethyl)phenoxybutyrate:

For analysis of enantiomeric purities of the product: a 10 μl samplesolution of approximately 1.0 mg/ml in concentration was injected onto aChiracel OD analytical column (4.6×250 mm, 10 micron). The column wasthen eluted with an isocratic solvent system consisting of 5%isopropanol in heptane at a flow rate of 0.5 ml/min. Peaks were recordedat the wavelength of 254 μm with an UV detector. Under these conditions,the retention time of the S enantiomer is approximately 10 minutes whilethe retention time of the R enantiomer is about 20 minutes. Enantiomericexcess (ee %) are calculated as area under curve of the S enantiomersubtract area under curve of the R enantiomer and divided by the sum ofthe two areas.

For preparative purpose, the Chiracel OD Semi-Prep column (20×250 mm, 10micron) was used. A 1.8 ml sample solution of approximately 40 mg/ml inconcentration was injected. The column was then eluted with an isocraticsolvent system consisting of 5% isopropanol in heptane at a flow rate of9.0 ml/min. Peaks detected above 0.5 mV threshold at the wavelength of254 μm were collected with a Gilson fraction collector. Fractionscontaining the S enantiomer were collected between 20-25 minutes afterinjection, while those containing the R enantiomer were collected atabout 40-45 minutes. Repeated injections resulted in continuousseparation of the two enantiomers. Fractions containing the separatedenantiomers were then combined, and concentrated to obtain the opticallyactive product as a clear oil. The enantiomeric purities of the materialranges from 96-99% ee

Ethyl(2R)-2-{3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy}butyrate

To a solution of3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indole (15 g, 50mmol) in DMF (300 mL) at 0 to 10° C., was added Cs₂CO₃ (45 g, 124 mmol)and ethyl (2R)-2-(3-bromomethyl)phenoxy butyrate (18 g, 50 mmol). Thereaction mixture was first stirred at 0 to 10° C. for 2 hours, then atroom temperature overnight. The mixture was diluted with water (400 ml),and extracted with ethyl acetate (2×150 ml). The organic extract waswashed with water (2×100 ml) and brine (100 ml), and dried overanhydrous MgSO₄, and concentrated under vacuum. The residue waschromatographed on silica gel with hexane/ethyl acetate (4:1) as thesolvent system to obtain the product as a white solid. ¹H NMR (CDCl₃,500 MHz) δ 7.76 (d, 2H), 7.48 (d, 2H), 7.36 (d, 1H), 7.25 (t, 1H), 7.15(s, 1H), 7.02 (d, 1H), 6.79 (d, 1H), 6.67 (d, 1H), 6.56 (s, 1H), 5.35(s, 2H), 4.49 (t, 1H), 4.21 (q, 2H), 2.55 (s, 3H), 1.97 (m, 2), 1.28 (t,3H), 1.07 (t, 3H). Enantiomeric purity of the product ranges from 98-99%ee based on analytical chiral HPLC analysis (Chiracel OD, 10% ethanol inheptane).

(2R)-2-{3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy}butyricacid:

To a solution of Ethyl(2R)-2-{3-[[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy}butyrate(23 g, 40 mmol) in tetrahydrofuran (THF, 200 ml) was added 200 ml ofmethanol and 160 ml of an 1N NaOH solution (160 mmol). The clearsolution was stirred at room temperature overnight, and neutralized (topH=4) with 2N HCl solution. The mixture was concentrated under reducedpressure to remove most of the organic solvent, and then stirred at roomtemperature for crystallization. The suspension was then filtered andthe solid washed with water and dried under vacuum to obtain the productas a white solid. ¹H NMR (CDCl₃, 500 MHz) δ 7.77 (d, 2H), 7.48 (d, 2H),7.35 (d, 1H), 7.27 (t, 1H), 7.17 (s, 1H), 7.02 (d, 1H), 6.84 (d, 1H),6.73 (d, 1H), 6.38 (s, 1H), 5.36 (q, 2H), 4.44 (t, 1H), 2.49 (s, 3H),1.98 (m, 2H), 1.07 (t, 3H). MS: (M+1)=546. Enantiomeric purity of theproduct ranges from 98-99% ee. (Chiralcel OD-RH, acetonitrile/watergradient).

Synthesis of a Compound where R³ is Phenoxy (Table 1)

Compounds in which R³ is phenoxy or thiophenoxy are shown in Table 1.The synthesis of a representative compound (Example 30) from Table 1 isshown in the scheme below, which is followed by a detailed descriptionof the synthesis. The other compounds in Table 1 can be synthesized byone of ordinary skill in the art by using similar synthetic strategiesand readily available materials.

Example 30

To a solution of 4-chlorophenol (15.36 g) in DMF (150 mL) at roomtemperature was added Cs₂CO₃ (64.4 g). After 15 min, chloroacetone (14.8mL) was introduced via syringe. The reaction mixture was stirred for 3hours, then partitioned between ether and water. The organic layer waswashed sequentially with water, 1N aqueous NaOH solution (2×), andbrine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.Distillation under high vacuum gave 14 g of the product as slightlyyellow oil. ¹H NMR (CDCl₃, 500 MHz) δ 7.28 (d, 2H), 6.83 (d, 2H), 4.54(s, 2H), 2.29 (s, 3H).

The above obtained ketone (12.89 g) and 3-trifluoromethoxyphenylhydrazine (12.22 g) were dissolved in benzene (50 mL). The reactionmixture was heated at 60° C. for 45 min, cooled to room temperature,dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to givethe phenylhydrazone (23 g), which was used immediately without furtherpurification.

To a solution of the above obtained hydrazone (23 g) in CH₂Cl₂ (200 mL)at room temperature was added PCl₃ (11 mL). The reaction was stirred atroom temperature for 24 h before water (3 mL) was introduced and thereaction was vigorously stirred for another 15 min. After cooling to 0°C. by an ice-water bath, the reaction was neutralized to pH 7 by adding5N aqueous NaOH solution. Most of the solvent was removed in vacuo. Theresidue was partitioned between ether and water. The organic layer waswashed with water and brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. Purification by flash chromatography (SiO₂,EtOAc/hex 25/1) gave the desired product (7.3 g) along with thecorresponding 4-trifluoromethoxyindole isomer (2.4 g). ¹H NMR (CDCl₃,500 MHz) δ 7.80 (s, broad, 1H), 7.24 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.4Hz, 1H), 7.19 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H),2.35 (s, 3H).

To a solution of the above obtained indole (3.16 g) and benzyl bromide(3.55 g) in DMF (40 mL) at room temperature was added Cs₂CO₃ (6.03 g).The reaction mixture was stirred for 15 h, poured into water, extractedwith EtOAc (2×). The combined organic layers were washed with water andbrine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.Purification by flash chromatography gave the desired product. ¹H NMR(CDCl₃, 500 MHz) δ 7.34 (d, J=8.2 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.25(d, J=9.0 Hz, 2H), 7.08 (s, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.92 (d, J=9.0Hz, 2H), 6.60 (dd, J=8.0, 1.7 Hz, 1H), 6.46 (d, J=1.7 Hz, 1H), 5.23 (s,2H), 4.62 (q, J=6.8 Hz, 1H), 3.85 (dd, J=6.8, 10.5 Hz, 1H), 3.70 (dd,J=6.8, 10.5 Hz, 1H), 2.24 (s, 3H), 1.81 (m, 1H), 1.64 (d, J=6.9 Hz, 3H),0.84 (d, J=6.6 Hz, 6H).

To a solution of the ester (5.0 g) in MeOH (200 mL) was added aqueousNaOH (1.0 N, 20 mL). The mixture was stirred at room temperature for 5h, cooled to 0° C., acidified with 1.0 N HCl, diluted with water (200mL), extracted with EtOAc (2×). The combined organic layers were washedwith water and brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by crystallization fromether/hexanes to give the product. ¹H NMR (CDCl₃, 500 MHz) δ 7.36 (d,J=8.2Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.25 (d, J=9.2Hz, 2H), 7.09 (s,1H), 6.96 (d, J=8.7 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.65 (d, J=8.0 Hz,1H), 6.45 (s, 1H), 5.26 (s, 2H), 4.63 (q, J=6.9 Hz, 1H), 2.24 (s, 3H),1.64 (d, J=6.9 Hz, 3H).

To a solution of phenol (10.23 g) in methylene chloride (200 mL) at roomtemperature were added alcohol (14.1 mL), PPh₃ (24.4 g), and DEAD (14.6mL). The reaction mixture was stirred overnight. The solvent was removedin vacuo. Purification by flash chromatography gave the desired product.¹H NMR (CDCl₃, 500 MHz) δ 7.25 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz,1H), 6.70 (s, 1H), 4.79 (q, J=6.7 Hz, 1H), 3.99 (m, 1H), 2.30 (s 3H),1.97 (m, 1H), 1.70 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.8 Hz, 6H).

To a solution of starting ester (15.3 g) in CCl₄ were added NBS (9.58 g)and catalytic AIBN (200 mg). The mixture was stirred at 80° C.overnight, cooled to room temperature, filtered, and concentrated invacuo. Purification by chromatography gave the desired benzyl bromide.¹H NMR (CDCl₃, 500 MHz) δ 7.35 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0, 2.0Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 4.84 (q, J=6.7 Hz, 1H), 4.43 (d, J=10.5Hz, 1H), 4.41 (d, J=10.5 Hz, 1H), 3.98 (m, 1H), 1.97 (m, 1H), 1.72 (d,J=6.9 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H).

Compounds in which R³ is Benzisoxazole (Table 2)

The synthesis of a compound in which R³ is benzisoxazole is shown in thescheme below, which is followed by a description of the procedure inExample 31. Other compounds in which R³ is benzisoxazole are show inTable 2. These can all be made by a skilled practitioner in syntheticorganic chemistry using the methods and strategies disclosed herein.

Example 31

(2R)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoicacid

Step 1. Methyl 2-(allyloxy)-4-methoxybenzoate (2):

To a solution of methyl 4-methoxysalicylate (2.0 g, 11 mmol) in DMF (20mL) at room temperature was added Cs₂CO₃ (1.3 eq, 4.7 g) and allylbromide (1.3 eq, 1.23 mL). After 2 hr, reaction mixture was diluted withEtOAc and washed with water (3×), brine (1×). The organic layer wasdried over Na₂SO₄ and concentrated to provide the product as a paleyellow oil. Product was used without further purification.

¹H NMR (500 MHz, CDCl₃): δ 7.89 (d, 1H), 6.53 (dd, 1H), 6.49 (d, 1H),6.08 (m, 1H), 5.55 (d, 1H), 5.33 (d, 1H), 4.63 (d, 2H), 3.89 (s, 3H),3.86 (s, 3H).Step 2. 2-(allyloxy)-4-methoxybenzoic acid (3):

To a solution of 2 (2.5 g, 11 mmol) in aqueous methanol (30 mL) wasadded KOH (1 eq, 630 mg). Reaction was heated to 50° C. for 12 hoursbefore the addition of more KOH (630 mg). After 12 hours, the mixturewas cooled, diluted with EtOAc and washed with 1M HCl. Aqueous layer wasextracted with EtOAc (3×). Combined organic layers, dried over Na₂SO₄,and concentrated. Product was isolated as an off white solid and usedwithout further purification.

¹H NMR (500 MHz, CD₃OD): δ 7.85 (d, 1H), 6.60 (m, 2H), 6.08 (m, 1H),5.49 (d, 1H), 5.30 (d, 1H), 4.68 (d, 2H), 3.84 (s, 3H).Step 3.[2-(allyloxy)-4-methoxyphenyl][2-methyl-6-(trifluoromethoxy)-1H-indol-3-yl]methanone(6):

To a slurry of 4 (6.34 g, 29 mmol) and ZnCl₂ (2.1 eq, 8.3 g) in CH₂Cl₂(220 mL) at ambient temperature was added EtMgBr (3.0M in ether). In aseparate flask, oxallyl chloride (1.3 eq, 3.3 mL) was added to asolution of 3 (1.1 eq, 6.8 g) in CH₂Cl₂ (200 mL). After 1 hour, thenewly formed acid chloride (5) solution was added via cannula to theindole. The reaction stirred for 1 hour before being quenched by pouringinto a solution of satd NH₄Cl. Layers were allowed to separate and thenthe organic layer was washed with NH₄Cl (2×) and NaHCO₃ (2×). Theorganic layer was dried over Na₂SO₄ before being filtered through a padof silica gel, eluting with 2:1 CH₂Cl₂/EtOAc. The filtrate wasconcentrated to provide a red solid which was triturated with MeOH(50-100 mL). The mother liquor was concentrated and the processrepeated. Product was isolated as a colored solid.

¹H NMR (500 MHz, CDCl₃): δ 8.48 (bs, 1H), 7.45 (d, 1H), 7.40 (d, 1H),7.16 (s, 1H), 6.97 (d, 1H), 6.60 (d, 1H), 6.52 (d, 1H), 5.67 (m, 1H),5.03 (d, 1H), 5.00 (s, 1H), 4.40 (d, 2H), 3.89 (s, 3H), 2.54 (s, 3H).Step 4.[2-(Allyloxy)-4-methoxyphenyl][2-methyl-1-[(4-methylphenyl)sulfonyl]-6-(trifluoromethoxy)-1H-indol-3-yl]methanone(7):

To a solution of 6 (8.0 g, 20 mmol) in DMF (200 mL) was added NaH (1.5eq). Mixture stirred for 15 min before addition of TsCl (1.5 eq, 5.6 g).After 1 hour, the reaction mixture was poured into ice water andextracted with CH₂Cl₂. The organic layer was washed with NH₄Cl (2×),NaHCO₃ and brine, then dried with Na₂SO₄ and concentrated. Purificationvia flash chromatography eluding with 20% EtOAc/hexanes afforded theproduct as a viscous yellow oil.

¹H NMR (500 MHz, CDCl₃): δ 8.17 (s, 1H), 7.75 (d, 2H), 7.58 (d, 1H),7.29 (d, 2H), 7.24 (d, 1H), 7.05 (d, 1H), 6.60 (dd, 1H), 6.42 (d, 1H),5.41 (m, 1H), 4.91 (m, 2H), 4.20 (d, 2H), 3.89 (s, 3H), 2.70 (s, 3H),2.41 (s, 3H).Step 5.(2-Hydroxy-4-methoxyphenyl)[2-methyl-1-[(4-methylphenyl)sulfonyl]-6-(trifluoromethoxy)-1H-indol-3-yl]methanone(8):

To a solution of 7 (9.0 g, 16 mmol), dimedone (1.5 eq, 3.4 g), andPd(PPh₃)₄ (5 mol %, 930 mg) in DMF (160 mL) was addeddiisopropylethylamine (1.5 eq, 4.2 mL). After 30 min, the reactionmixture was diluted with DCM and washed with 0.05M HCl (3×), NaHCO₃, andbrine. The organic layer was dried with Na₂SO₄ then filtered through apad of silica gel to remove remaining palladium. Product was purifiedvia flash chromatography eluding with 14% EtOAc/hexanes to provide theproduct as an amorphous yellow solid contaminated with ˜10% allylateddimedone. Product was used without further purification.

¹H NMR (500 MHz, CDCl₃): δ 12.66 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H),7.32 (d, 1H), 7.30 (m, 3H), 7.14 (d, 1H), 6.52 (d, 1H), 6.37 (dd, 1H),3.89 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H).Step 6.(2-Hydroxy-4-methoxyphenyl)[2-methyl-1-[(4-methylphenyl)sulfonyl]-6-(trifluoromethoxy)-1H-indol-3-yl]methanoneoxime (9):

A solution of 8 (16 mmol), hydroxylamine hydrochloride (10 eq, 11.2 g)and pyridine (270 mL) was heated to 80° C. for 24 hours. Additionalhydroxylamine (3 g) was added and the temperature increased to 90° C.After LC analysis confirmed the consumption of starting material, thereaction was cooled and the pyridine removed by rotary evaporation. Theresidue was dissolved in DCM and washed with water and 1M HCl. Theorganic layer was dried over Na₂SO₄ and concentrated. The reactionmixture was purified by flash chromatography eluding with 20%EtOAc/hexanes, Rf=0.4. The product was isolated as a white foam.

¹H NMR (500 MHz, CDCl₃): δ 8.15 (s, 1H), 7.71 (d, 2H), 7.45 (bs, 1H),7.27 (d, 2H), 7.09 (m, 2H), 6.56 (m, 2H), 6.23 (dd, 1H), 3.79 (s, 3H),2.47 (s, 3H), 2.40 (s, 3H).Step 7.6-Methoxy-3-[2-methyl-1-[(4-methylphenyl)sulfonyl]-6-(trifluoromethoxy)-1H-indol-3-yl]-1,2-benzisoxazole(10):

To a solution of 9 (3.8 g, 7.1 mmol) and NaOAc (3 eq, 1.8 g) in DMF (120mL) was added Ac₂O (3 eq, 2 mL). The reaction was heated to 110° C. for4 hours at which time no starting material was detected by LC analysis.The reaction was cooled and diluted with DCM. The solution was washedwith NH₄Cl, brine and NaHCO₃, then dried over Na₂SO₄ and concentrated.The residue was purified via flash chromatography eluding with 20%EtOAc/hexanes. Product was isolated as white foam.

¹H NMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.77 (d, 2H), 7.48 (d, 1H),7.36 (d, 1H), 7.28 (d, 2H), 7.15 (d, 1H), 7.09 (d, 1H), 6.94 (dd, 1H),3.92 (s, 3H), 2.74 (s, 3H), 2.39 (s, 3H).Step 8.6-Methoxy-3-[2-methyl-6-(trifluoromethoxy)-1H-indol-3-yl]-1,2-benzisoxazole(11):

K₂CO₃ (3 eq) and 10 (2.5 g, 4.8 mmol) were heated to reflux in aqueousmethanol for 2 hours at which time starting material had been consumed.The reaction mixture was concentrated, diluted with EtOAc and washedwith brine. The organic layer was dried over Na₂SO₄ and concentrated.The residue was purified via flash chromatography eluding with 20%EtOAc/hexanes to provide the product as a pale green solid.

¹H NMR (500 MHz, CDCl₃): δ 8.45 (bs, 1H), 7.62 (d, 1H), 7.56 (d, 1H),7.25 (s, 1H), 7.09 (d, 1H), 7.05 (d, 1H), 6.94 (dd, 1H), 3.93 (s, 3H),2.63 (s, 3H).Step 9. Methyl(2R)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoate(15):

A mixture of 11 (208 mg, 0.57 mmol), Cs₂CO₃ (3 eq, 500 mg), 14 (1.1 eq,202 mg) and DMF (4 mL) were combined at rt and stirred for 15 hours. Thereaction mixture was diluted with EtOAc and washed with 1M HCl (2×). Theorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified via flash chromatography eluding with 5-15% EtOAc/hexanes.Isolated product was a white foam.

¹H NMR (500 MHz, CDCl₃): δ 7.71 (d, 1H), 7.60 (d, 1H), 7.34 (d, 1H),7.11 (m, 3H), 6.96 (dd, 1H), 6.72 (dd, 1H), 5.94 (d, 1H), 5.40 (s, 2H),4.41 (q, 1H), 3.93 (s, 3H), 3.49 (s, 3H), 2.54 (s, 3H), 1.44 (d, 3H).Step 10.(2R)-2-(4-Chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoicacid (16):

To a solution of 15 (312 mg, 0.46 mmol) in aqueous methanol was added asolution of 1.0M NaOH (1.5 eq). After 2 hours, reaction was complete byTLC. The solution was concentrated and purified by preparatory LC (C18,100×20 mm I.D., 5 um). Product was isolated as a white amorphous solid.

¹H NMR (600 MHz, CDCl₃): δ 7.60 (d, 1H), 7.56 (d, 1H), 7.34 (d, 1H),7.17 (s, 1H), 7.09 (m, 2H), 6.99 (dd, 1H), 6.80 (dd, 1H), 5.61 (d, 1H),5.41 (dd, 2H), 4.22 (q, 1H), 3.94 (s, 3H), 2.41 (s, 3H), 1.46 (d, 3H).t_(R)=4.34min, 575.1 (M+H).Step 11. Methyl (2R)-2-(4-chloro-3-methylphenoxy)propanoate (13):

To a solution of 3-methyl-4-chlorophenol (10.0 g, 69 mmol),triphenylphosphine (1.3 eq, 22 g), (S)-methyl lactate (1.3 eq, 9.4 mL)in DCM (230 mL) at 0° C. was added DEAD (1.2 eq, 13 mL) over 1 min.Reaction warmed to rt overnight. The mixture was then filtered through apad of silica gel and concentrated. The residue was purified via flashchromatography eluting with 10% EtOAc/hexanes to provide the product asa colorless oil.

¹H NMR (500 MHz, CDCl₃): δ 7.19 (d, 1H), 6.76 (d, 1H), 6.63 (dd, 1H),4.71 (q, 1H), 3.75 (s, 3H), 2.31 (s, 3H), 1.60 (d, 3H).Step 12. Methyl (2R)-2-[3-(bromomethyl)-4-chlorophenoxy]propanoate (14):

To a solution of lactate (15.8 g, 69 mmol) in CCl₄ (150 mL) was addedNBS (1.1 eq, 13.5 g) and AIBN (100 mg). The reaction mixture was heatedto reflux for 24 hours. The solution was filtered through a pad ofsilica gel and concentrated. The residue was purified via flashchromatography eluding with 5% EtOAc/hexanes to provide the product as awhite solid.

¹H NMR (500 MHz, CDCl₃): δ 7.27 (d, 1H), 6.96 (d, 1H), 6.76 (dd, 1H),4.74 (q, 1H), 4.52 (s, 2H), 3.77 (s, 3H), 1.62 (d, 3H).

Synthesis of Compounds in which R³ is Phenyl

A synthetic method is shown below in Example 32 for a compound in whichR³is phenyl. This and other compounds in which R³ is phenyl are shown inTable 4. The other compounds in Table 4 were synthesized using themethods and strategies described herein and readily available materials.Such synthetic methods and materials are readily apparent to apractitioner in the field of synthetic chemistry.

Example 32

4-Methoxyphenylacetone (1.12 g) and 3-trifluoromethoxyphenyl hydrazine(0.96 g) were dissolved in benzene (20 mL). The reaction mixture washeated at 60° C. for 45 min, cooled to room temperature, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo to give thephenylhydrazone, which was used immediately without furtherpurification.

To a solution of the above obtained hydrazone (2.0 g) in CH₂Cl₂ (100 mL)at room temperature was added PCd₃ (0.76 mL). The reaction was stirredat room temperature for 24 h. After cooling to 0° C. by an ice-waterbath, the reaction was neutralized to pH 7 by adding 5N aqueous NaOHsolution. Most of the solvent was removed in vacuo. The residue waspartitioned between ether and water. The organic layer was washed withwater and brine, dried over anhydrous MgSO₄, filtered, and concentratedin vacuo. Purification by flash chromatography (SiO₂, EtOAc/hex 25/1)gave 6-trifluoromethoxy product A (1.0 g) along with the corresponding4-trifluoromethoxyindole isomer B (0.5 g).

Isomer A: ¹H NMR (CDCl₃, 500 MHz) δ 8.01 (s, broad, 1H), 7.56 (d, J=8.7Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.02 (d, J=8.7 Hz, 2H),6.99 (d, J=8.7 Hz, 1H), 3.88 (s, 3H), 2.49 (s, 3H).

Isomer B: ¹H NMR (CDCl₃, 500 MHz) δ 8.09 (s, broad, 1H), 7.31 (d, J=8.7Hz, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.1 (t, J=8.0 Hz, 1H), 6.96(overlapping signals, 3H), 3.87 (s, 3H), 2.39 (s, 3H).

To a solution of indole B (1.0 g) and benzyl bromide (1.0 g) in DMF (40mL) at room temperature was added Cs₂CO₃ (2.0 g). The reaction mixturewas stirred for 15 h, poured into water, extracted with EtOAc (2×). Thecombined organic layers were washed with water and brine, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo. Purification byflash chromatography gave the coupling product.

To a solution of the above obtained ester (1.5 g) in MeOH (100 mL) wasadded aqueous NaOH (1.0 N, 10 mL). The mixture was stirred at roomtemperature for 5 h, cooled to 0° C., acidified with 1.0 N HCl, dilutedwith water (200 mL), extracted with EtOAc (2×). The combined organiclayers were washed with water and brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The residue was purified bycrystallization from ether/hexanes to give the product.

¹H NMR (CDCl₃, 500 MHz) δ 7.32 (d, J=8.5 Hz, 2H), 7.23 (t, J=8.0 Hz,1H), 7.17 (d, J=8.2 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.96 (d+d,overlapping signals, 3H), 6.78 (d, J=8.2 Hz, 1H), 6.66 (d, J=7.6Hz, 1H),6.58 (s, 1H), 5.34 (s, 2H), 4.53 (t, J=6.0 Hz, 1H), 3.87 (s, 3H), 2.29(s, 3H), 1.99 (m, 2H), 1.06 (t, J=7.4 Hz, 3H). TABLE 1 Compounds WhereR³ is Phenoxy or Thiophenoxy MOLSTRUCTURE PARENT WEIGHT Mass SpecRetention Time 1

533.936 M + H 4.45 2

431.558 432 4.15 3

451.976 452 4.14 4

451.976 452 4.21 5

547.963 M + H 4.51 6

533.936 M + H 4.45 7

535.974 536 4.7  8

529.518 M + H 4.18 9

529.518 M + H 4.21 10

519.909 M + H 4.49 11

479.965 M + H 4.18 12

479.965 M + H 4.21 13

547.963 4.51 548 (M + 1) 14

492.02 15

492.02 16

499.491 500 (M + 1) 3.8 min  17

499.491 500 (M + 1) 3.8 min  18

499.491 500 (M + 1) 3.99 min 19

499.491 500 (M + 1) 4.06 min 20

519.909 M + H 4.49 21

533.936 M + H 4.32 22

533.936 M + H 4.32 23

467.929 M + H 4.26 24

467.929 M + H 4.26 25

467.929 M + H 4.16 26

467.929 M + H 4.13 27

513.518 514.4 (M + 1) 3.87 28

513.518 514.4 (M + 1) 3.87 29

513.518 514.3 (M + 1) 3.65 30

513.518 514.4 (M + 1) 3.65 31

527.545 528.4 (M + 1) 3.95 32

527.545 528.4 (M + 1) 3.95 33

527.545 528.4 (M + 1) 4.56 34

527.545 528.4 (M + 1) 4.56 35

568.381 M + H 4.79 36

582.408 M + H 4.89 37

547.963 548 (M + 1) 4.19 min 38

533.936 534 (M + 1) 4.06 min 39

533.936 534 (M + 1) 3.93 min 40

547.963 548 (M + 1) 4.18 min 41

561.99 562 (M + 1) 4.26 min 42

545.536 546 (M + 1) 4.14 min 43

531.509 532 (M + 1) 4.08 min 44

554.354 M + H 4.64 45

568.381 46

517.482 518 (M + 1) 3.78 min 47

533.936 534 (M + 1) 3.96 min 48

517.482 518 (M + 1) 3.85 min 49

517.482 518 (M + 1) 3.91 min 50

517.482 518 (M + 1) 3.91 min 51

554.354 M + H 4.5  52

568.381 M + H 4.78 53

551.927 M + H 4.63 54

515.491 M + H 4.13 55

533.936 M + H 4.59 56

554.354 M + H 4.65 57

584.446 584 4.74 58

598.473 598 5.05 59

598.473 598 5.02 60

519.909 61

519.909 62

550.001 550.3 (M + H) 4.35 min 63

517.937 518.4 (M + 1) 4.17 64

517.937 518.4 (M + 1) 4.17 65

601.935 66

547.963 548 (M + 1) 4.18 min 67

517.937 518 (M + 1) 4.12 min 68

547.963 548 (M + 1) 4.18 min 69

545.536 546 (M + 1) 4.34 min 70

545.536 546 (M + 1) 4.34 min 71

531.509 532 (M + 1) 4.19 min 72

531.509 532 (M + 1) 4.21 min 73

553.964 554.3 4.23 74

553.964 554.3 4.23 75

553.964 554.3 (M + H) 4.22 76

553.964 554.3 (M + H) 4.23 77

570.419 570.3 (M + H) 4.35 78

570.419 570.3 (M + H) 4.36 79

531.964 532 (M + 1) 4.65 min 80

531.964 532 (M + 1) 4.65 min 81

513.518 514 (M + 1) 4.14 min 82

659.833 M + H 4.43 83

527.545 528.4 (M + 1) 4.02 84

527.545 528.4 (M + 1) 4.02 85

566 566.3 (M + H) 3.52 86

519.909 M + H 4.33 87

521.9 522.4 (M + 1) 4.08 88

538.355 538.4 (M + 1) 4.13

TABLE 1A Compounds Where R³ is Phenoxy or Thiophenoxy 1(2R)-2-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 2(2R)-2-(3-{[2-methyl-3-(phenylthio)-1H-indol-1-yl]methyl}phenoxy)butanoicacid 3(2S)-2-(2-chloro-5-{[2-methyl-3-(phenylthio)-1H-indol-1-yl]methyl}phenoxy)propanoicacid 4(2R)-2-(4-chloro-3-{[2-methyl-3-(phenylthio)-1H-indol-1-yl]methyl}phenoxy)propanoicacid 52-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 62-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 7(2S)-2-(3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 82-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 92-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 10(2S)-2-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 112-(3-{[3-(4-chlorophenoxy)-6-methoxy-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 122-(3-{[3-(4-chlorophenoxy)-6-methoxy-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 132-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 142-(3-{[3-(4-chlorophenoxy)-6-isopropyl-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 152-(3-{[3-(4-chlorophenoxy)-6-isopropyl-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 16(2R)-2-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 17(2S)-2-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 18(2R)-2-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 19(2S)-2-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 20(2R)-2-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 212-(3-{[3-(4-chlorophenoxy)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 222-(3-{[3-(4-chlorophenoxy)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 232-(3-{[3-(4-chlorophenoxy)-6-fluoro-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 242-(3-{[3-(4-chlorophenoxy)-6-fluoro-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 252-(3-{[3-(4-chlorophenoxy)-4-fluoro-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 262-(3-{[3-(4-chlorophenoxy)-4-fluoro-2-methyl-1H-indol-1-yl]methyl}phenoxy)butanoicacid 272-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 282-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 292-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 302-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 312-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 322-(3-{[3-(4-methoxyphenoxy)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 332-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 342-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 352-(4-chloro-3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 362-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 372-(4-chloro-3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 38(2S)-2-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 39(2S)-2-(4-chloro-3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 402-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 412-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 422-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 432-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 442-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 452-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 46(2S)-2-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 47(2R)-2-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 48(2R)-2-(4-fluoro-3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 49(2S)-2-(4-fluoro-3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 50(2R)-2-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 51(2S)-2-(4-chloro-3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 522-(4-chloro-3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 532-(5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)butanoic acid 54(2S)-2-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 552-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 56(2R)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 572-(4-chloro-3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 582-(4-chloro-3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 592-(4-chloro-3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 602-{3-[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 612-{3-[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 62(2R)-2-(3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 632-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 642-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 653-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid 662-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 672-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 682-(2-chloro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 692-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 702-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 712-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 722-(2-fluoro-5-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 73(2S)-2-(3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-fluorophenoxy)propanoic acid 74(2R)-2-(3-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-fluorophenoxy)propanoic acid 75(2S)-2-(5-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)propanoic acid 76(2R)-2-(5-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)propanoic acid 77(2S)-2-(2-chloro-5-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 78(2R)-2-(2-chloro-5-{[3-[(4-chlorophenyl)thio]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 792-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 802-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 812-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 82(2R)-2-(3-{[3-(4-chlorophenoxy)-5-iodo-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 832-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 842-(3-{[3-(4-methoxyphenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 85(2R)-2-(3-{[3-[(4-chlorophenyl)sulfinyl]-2-methyl-5-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 862-{3-[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 87(2S)-2-(3-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}-4-fluorophenoxy)propanoic acid 88(2S)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)propanoic acid

TABLE 2 Compounds Where R³ is Benzisoxazole MOLSTRUCTURE PARENT WEIGHTMass Spec Retention Time 1

540.501 541.1 (M + H) 3.91 2

544.919 545.3 (M + H) 4.41 3

544.919 545.3 (M + H) 4.41 4

540.501 541.1 (M + H) 4.09 5

540.501 541.1 (M + H) 4.06 6

540.501 541.1 (M + H) 4.11 7

574.946 575.4 (M + H) 4.28 8

574.946 575.1 (M + H) 4.34 9

574.946 575.4 (M + H) 4.27 10

526.473 11

540.501 12

526.473 13

540.501 14

554.528 555.2 (M + H) 3.79 15

554.528 555.2 (M + H) 3.96 16

568.555 569.4 (M + H) 4.36 17

579.364 579.1 (M + H) 4.49 18

579.364 579.1 (M + H) 4.48 19

579.364 579.3 4.6  20

558.946 559.1 (M + H) 4.44 21

558.946 559.3 (M + H) 4.54 22

574.946 575.3 (M + H) 4.31 23

540.501 24

540.501 25

588.973 589.1 (M + H) 4.35 26

588.973 589.1 (M + H) 4.35 27

568.555 569.2 (M + H) 4.30 min 28

568.555 569.2 (M + H) 4.30 min 29

568.555 569.2 (M + H) 4.29 min 30

579.364 579.1 4.49 min 31

593.391 593.1 4.61 min 32

593.391 593.1 4.62 min 33

562.909 563.1 4.34 min 34

562.909 563.1 4.33 min 35

562.909 563.1 4.34 min 36

562.909 563.1 4.33 min 37

558.491 559.0 4.05 min 38

558.491 559.1 4.05 min 39

588.973 589.3 4.51 min 40

558.491 559.3 4.11 min 41

558.491 559.3 4.11 min 42

603 603.4 4.58 min 43

603 603.0 4.58 min 44

603 603.4 4.58 min 45

603 603.4 4.59 min 46

603 603.4 4.57 min 47

603 603.4 4.56 min

TABLE 2A Compounds Where R³ is Benzisoxazole 1(2S)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 2(2S)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 3(2R)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 4(2R)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 5(2S)-2-(3-{[3-(7-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 6(2R)-2-(3-{[3-(7-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 7(2R)-2-(2-chloro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 8(2R)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 9(2S)-2-(2-chloro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 10(2S)-2-{3-[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 11(2R)-2-{3-[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 12(2R)-2-{3-[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 13(2S)-2-{3-[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 14(2S)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 15(2R)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 16(2R)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 17(2S)-2-(4-chloro-3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 18(2S)-2-(2-chloro-5-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 19(2R)-2-(4-chloro-3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 20(2S)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 21(2R)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 22(2S)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 23(2S)-2-(3-{[3-(5-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 24(2R)-2-(3-{[3-(5-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 25(2R)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 26(2S)-2-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 272-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 282-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 29(2S)-2-(3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 30(2R)-2-(2-chloro-5-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 31(2S)-2-(4-chloro-3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 32(2R)-2-(4-chloro-3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 33(2S)-2-(5-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)propanoic acid 34(2R)-2-(5-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)propanoic acid 35(2S)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-fluorophenoxy)propanoic acid 36(2R)-2-(3-{[3-(6-chloro-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-fluorophenoxy)propanoic acid 37(2S)-2-(2-fluoro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 38(2R)-2-(2-fluoro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 392-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 40(2S)-2-(4-fluoro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 41(2R)-2-(4-fluoro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 422-(2-chloro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 432-(2-chloro-5-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 442-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 452-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 462-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 472-(4-chloro-3-{[3-(6-methoxy-1,2-benzisoxazol-3-yl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid

TABLE 3 Compounds Where R³ is Benzoyl MOLSTRUCTURE PARENT WEIGHT MassSpec Retention Time 1

443.504 444.1 (M + H) 3.44 min 2

527.502 528.1 (M + H) 3.87 min 3

531.92 532.0 (M + H) 4.11 min 4

527.502 528.1 3.75 min 5

527.502 528.1 (M + H) 3.77 min 6

513.475 514.0 (M + 1) 3.88 min 7

541.529 542.0 (M + H) 3.91 min 8

527.502 528.2 (M + 1) 3.96 min 9

511.502 512 (M + 1) 3.95 10

555.556 11

609.527 12

531.92 532.0 (M + 1) 4.33 min 13

532.908 533.1 (M + 1) 3.95 min 14

542.516 543.1 (M + 1) 4.12 min 15

497.475 16

595.5 17

532.908 533.1 (M + 1) 3.70 min 18

512.49 513.2 (M + 1) 3.23 min 19

548.523 549.2 (M + 1) 4.02 min 20

599.919 M + H 4.43 21

546.935 22

548.523 549.2 (M + 1) 3.76 min 23

561.947 M + H 3.99 24

574.002 574 (M + 1) 4.28 25

574.002 574 (M + 1) 4.28 26

566.365 M + H 4.3  27

547.92 M + H 4.08 28

561.947 M + H 3.99 29

566.365 M + H 4.3  30

561.947 M + H 4.04 31

566.365 M + H 4.32 32

552.338 33

552.338 34

561.947 M + H 4.04 35

566.365 M + H 4.32 36

545.947 545 4.19 37

566.365 566 (M + 1) 4.09 38

566.365 566 (M + 1) 4.09 39

553.54 554 (M + 1) 3.96 40

557.959 558 (M + 1) 4.01 41

553.54 554 (M + 1) 3.95 42

517.893 518.2 (M + 1) 4.17 min 43

517.893 518.2 (M + 1) 4.18 min 44

557.959 558 (M + 1) 3.89 45

561.947 562 (M + 1) 3.87 46

561.947 562 (M + 1) 3.88 47

545.947 546 (M + 1) 4.13 48

545.947 546 (M + 1) 4.13 49

600.04 M + 1 = 600 4.68 50

545.947 M + 1 = 546 4.21 51

574.002 M + 1 = 574 4.49 52

559.975 M + 1 = 560 4.4  53

593.992 M + 1 = 594 4.26 54

557.959 M + 1 = 558 4.28 55

531.92 532.3 (M + H) 4.09 min 56

559.975 M + 1 = 560 4.35 57

541.529 542 (M + 1) 3.87 58

541.529 542 (M + 1) 3.82 59

545.947 M + 1 = 546 4.2  60

545.947 M + 1 = 546 4.2  61

559.975 M + 1 = 560 4.36 62

559.975 M + 1 = 560 4.36 63

567.567 M + H 4.05 64

571.986 M + H 4.29 65

606.431 M + H 4.39 66

567.567 568 (M + 1) 3.92 67

571.986 571 (M + 1) 3.88 68

600.81 602 (M + 1) 4.18 69

600.81 602 (M + 1) 4.18 70

534.496 535.2 (M + 1) 3.83 min 71

534.496 535.2 (M + 1) 3.84 min 72

531.92 73

580.392 580 (M + 1) 4.22 74

580.392 580 (M + 1) 4.22 75

594.42 594 (M + 1) 4.36 76

594.42 594 (M + 1) 4.36 77

545.947 78

559.975 M + 1 = 560 4.36 79

559.975 M + 1 = 560 4.36 80

580.392 580 (M + 1) 3.78 81

575.974 M + H 4.13 82

580.392 M + H 4.34 83

594.42 594 (M + 1) 3.96 84

594.42 M + H 4.6  85

575.974 580 (M + 1) 3.88 86

590.001 590 (M + 1) 3.96 87

614.837 614 (M + 1) 3.77 88

628.865 628 (M + 1) 3.82 89

561.947 562 (M + 1) 2.26 90

561.947 562 (M + 1) 2.26 91

559.975 M + 1 = 560 4.31 92

574.002 M + 1 = 574 4.48 93

574.002 M + 1 = 574 4.46 94

590.001 M + H 4.26 95

594.42 M + H 4.61 96

604.028 M + H 4.37 97

608.447 M + H 4.56 98

604.028 M + H 4.34 99

618.055 M + H 4.45 100

608.447 M + H 4.72 101

622.474 M + H 4.86 102

620.337 620 (M + 1) 4.19 103

575.974 576 (M + 1) 3.93 104

559.975 M + 1 = 560 4.31 105

559.975 M + 1 = 560 4.31 106

575.974 M + H 4.17 107

575.974 M + H 4.17 108

573.546 574 (M + 1) 3.91 109

573.546 574 (M + 1) 3.92 110

573.546 574 (M + 1) 3.92 111

555.948 556.2 (M + H) 3.96 min 112

539.557 M + H 4.04 113

543.975 M + H 4.36 114

569.539 115

587.601 M + H 4.12 116

592.02 M + H 4.43 117

573.546 574 (M + 1) 3.96 118

577.965 578 (M + 1) 4.12 119

590.001 590 (M + 1) 4.01 120

594.42 594 (M + 1) 3.89 121

525.529 M + H 3.88 122

529.948 M + H 4.23 123

577.965 578 (M + 1) 4.02 124

561.557 562.0 (M + 1) 4.37 min 125

515.466 M + H 3.87 126

581.473 M + H 4.2  127

513.905 514.2 (M + H) 4.03 min 128

547.92 548.2 (M + H) 3.52 min 129

569.975 570.0 (M + H) 4.14 min 130

541.529 M + 1 = 542 3.92 131

559.519 560 (M + 1) 3.82 132

559.519 560 (M + 1) 3.82 133

563.938 564 (M + 1) 3.85 134

563.938 564 (M + 1) 3.85 135

599.919 600 (M + 1) 4.21 136

559.975 M + H 4.42 137

559.975 M + H 4.42 138

549.911 550.0 (M + 1) 4.33 min 139

535.884 536.1 (M + 1) 4.16 min 140

535.884 536.1 (M + 1) 4.15 min 141

555.556 M + 1 = 556 4.01 142

569.583 M + 1 = 570 4.22 143

574.002 144

574.002 M + Na 4.43 145

574.002 M + H 4.4  146

574.002 M + H 4.4  147

588.029 M + H 4.51 148

588.029 M + H 4.51 149

574.002 M + H 4.43 150

574.002 M + H 4.43 151

617.909 618 (M + 1) 4.28 152

549.911 550.2 (M + 1) 4.36 min 153

535.884 535.9 (M + 1) 4.27 min 154

535.884 536.1 (M + 1) 4.21 min 155

532.908 533.1 (M + 1) 4.24 min 156

575.974 M + 1 + Na = 598 4.25 157

580.392 M + 1 = 580 4.34 158

561.947 M + 1 + Na = 584 3.96 159

624.843 M − Br = 544 4.86 160

595.5 M + H 4.24 161

595.5 M + H 4.24 162

609.527 163

609.527 164

447.923 448 3.66 min 165

447.923 448.1 3.63 min 166

443.504 444.1 3.32 min 167

539.557 M + H 4.05 168

528.489 529.2 (M + 1) 3.94 min 169

580.392 M + 1 = 580 4.43 170

563.938 M + 1 = 564 4.27 171

573.593 574.1 3.43 min 172

589.592 590.3 3.61 min 173

557.593 558 4.24 min 174

543.566 543.9 3.87 min 175

543.566 544.1 3.61 min 176

527.502 528.4 (M + 1) 3.73 min 177

531.92 532.4 (M + 1) 3.99 min 178

531.465 532.3 (M + 1) 3.63 min 179

549.911 550.3 (M + 1) 4.03 min 180

181

182

183

184

185

186

187

188

189

TABLE 3A Compounds Where R³ is Benzoyl 1(2S)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-1H-indol-1-yl]methyl}phenoxy)propanoicacid 2(2S)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 3(2S)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 4(2S)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-5-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 5(2R)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 6(2S)-2-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 72-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 82-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 93-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)propanoic acid 102-ethoxy-3-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)propanoic acid 113-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid 122-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 132-{3-[3-[(6-chloropyridin-3-yl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 142-{3-[3-[(6-ethoxypyridin-3-yl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 153-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenyl}propanoic acid 163-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenyl}-2-(2,2,2-trifluoroethoxy)propanoic acid 172-{3-[3-[(2-chloropyridin-3-yl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 182-methyl-2-{3-[2-methyl-3-[(6-methylpyridin-2-yl)carbonyl]-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 192-methyl-2-{3-[2-methyl-3-(quinolin-2-ylcarbonyl)-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 203-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenyl}-2-(2,2,2-trifluoroethoxy)propanoic acid 212-{3-[3-(2-chloro-6-methylisonicotinoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 222-{3-[3-(isoquinolin-1-ylcarbonyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic acid 23(2S)-2-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 24(2S)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-propylphenoxy)propanoic acid 25(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-propylphenoxy)propanoic acid 26(2S)-2-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 27(2S)-2-{2-chloro-5-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 28(2R)-2-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 29(2R)-2-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 30(2S)-2-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 31(2S)-2-(4-chloro-3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 32(2R)-2-{2-chloro-5-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 33(2S)-2-{2-chloro-5-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 34(2R)-2-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 35(2R)-2-(4-chloro-3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 36(2S)-2-(3-{1-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]ethyl}phenoxy)propanoic acid 37(2S)-2-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 38(2R)-2-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 392-ethyl-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2,3-dihydro-1-benzofuran-2-carboxylic acid 405-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid 416-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-methylchromane-2-carboxylic acid 42(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 43(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 446-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-methylchromane-2-carboxylic acid 45(2S)-2-(3-{[3-(4-chloro-2-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 46(2R)-2-(3-{[3-(4-chloro-2-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 47(2S)-2-(3-{[3-(4-chloro-2-methylbenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 48(2R)-2-(3-{[3-(4-chloro-2-methylbenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 49(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)(cyclohexyl)acetic acid 502-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 512-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-4-methylpentanoic acid 522-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 53(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)(phenyl)acetic acid 541-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)cyclobutanecarboxylic acid 55(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 562-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 57(2S)-2-(3-{[3-(4-methoxy-2-methylbenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 58(2R)-2-(3-{[3-(4-methoxy-2-methylbenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 59(2S)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 60(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 612-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 622-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 63(2R)-2-ethyl-7-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}chromane-2-carboxylic acid 64(2R)-7-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-ethylchromane-2-carboxylic acid 65(2R)-7-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-ethylchromane-2-carboxylic acid 66(2S)-2-ethyl-7-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}chromane-2-carboxylic acid 67(2S)-7-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-ethylchromane-2-carboxylic acid 68(2S)-2-(3-{[2-methyl-3-(2,4,6-trichlorobenzoyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 69(2R)-2-(3-{[2-methyl-3-(2,4,6-trichlorobenzoyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 70(2S)-2-{3-[2-methyl-3-(quinolin-2-ylcarbonyl)-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 71(2R)-2-{3-[2-methyl-3-(quinolin-2-ylcarbonyl)-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 722-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 732-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 742-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 752-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 762-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 772-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}pentanoic acid 782-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 792-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 802-(4-chloro-3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 812-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 822-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 832-(4-chloro-3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 842-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 852-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 862-(4-chloro-3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 872-(4-chloro-3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 882-(4-chloro-3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 89(2R)-2-(3-{[3-(2-chloro-4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 90(2S)-2-(3-{[3-(2-chloro-4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 912-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 922-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 932-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpentanoic acid 942-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 952-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 962-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpentanoic acid 972-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpentanoic acid 982-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-ethylbutanoic acid 992-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-ethylpentanoic acid 1002-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-ethylbutanoic acid 1012-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-ethylpentanoic acid 1022-(3-{[3-(2,4-dichlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3,3,3-trifluoropropanoic acid 1032-(3-{[3-(2-chloro-4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1042-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 1052-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 1062-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1072-(2-cbloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1082-(2-fluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 1092-(2-tluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 1102-(2-fluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)pentanoic acid 111(4-chlorophenyl)[2-methyl-1-{3-[(1S)-1-(2H-tetrazol-5-yl)ethoxy]benzyl}-6-(trifluoromethoxy)-1H-indol-3-yl]methanone 1122-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}benzyl)butanoic acid 1132-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}benzyl)butanoic acid 114(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}benzyl)(methyl)malonic acid 1153-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-phenylpropanoic acid 1163-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-phenylpropanoic acid 1172-(2-fluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1182-(5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)-3-methylbutanoic acid 1192-(2-chloro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1202-(2-chloro-5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1213-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-methylpropanoic acid 1223-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2-methylpropanoic acid 1232-(5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)pentanoic acid 124(2S)-2-{5-[3-[4-(ethylthio)benzoyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-2-fluorophenoxy}propanoic acid 125(2R)-2-(3-{[3-(4-fluorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 126(2R)-2-[3-({2-methyl-6-(trifluoromethoxy)-3-[4-(trifluoromethoxy)benzoyl]-1H-indol-1-yl}methyl)phenoxy]propanoic acid 127(2E)-3-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)acrylic acid 128(2S,3R)-3-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)-2,3-dihydroxypropanoic acid 129(4-chlorophenyl)[2-methyl-1-{3-[1-(2H-tetrazol-5-yl)propoxy]benzyl}-6-(trifluoromethoxy)-1H-indol-3-yl]methanone 130(2R)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1312-(2-fluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1322-(2-fluoro-5-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1332-(5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)butanoic acid 1342-(5-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-2-fluorophenoxy)butanoic acid 1352-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-4,4,4-trifluorobutanoic acid 136(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 137(2S)-2-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1382-{5-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-2-fluorophenoxy}-2-methylpropanoic acid 139(2S)-2-{5-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-2-fluorophenoxy}propanoic acid 140(2R)-2-{5-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-2-fluorophenoxy}propanoic acid 1412-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylbutanoic acid 1422-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpentanoic acid 1432-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1442-(3-{[3-(4-chlorobenzoyl)-2-isopropyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1452-(3-{[3-(4-chlorobenzoyl)-2-propyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1462-(3-{[3-(4-chlorobenzoyl)-2-propyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1472-(3-{[3-(4-chlorobenzoyl)-2-propyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1482-(3-{[3-(4-chlorobenzoyl)-2-propyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1492-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1502-(3-{[3-(4-chlorobenzoyl)-2-ethyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 1512-(3-{[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}-4-fluorophenoxy)-4,4,4-trifluorobutanoic acid 1522-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}-2-methylpropanoic acid 153(2S)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}propanoic acid 154(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}propanoic acid 1552-({6-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridin-2-yl}oxy)-2-methylpropanoic acid 1562-(3-{[3-(4-chlorobenzoyl)-2-(methoxymethyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1572-(3-{[3-(4-chlorobenzoyl)-2-(chloromethyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1582-(3-{[3-(4-chlorobenzoyl)-2-(hydroxymethyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1592-(3-{[2-(bromomethyl)-3-(4-chlorobenzoyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1602-[3-({2-methyl-6-(trifluoromethoxy)-3-[4-(trifluoromethoxy)benzoyl]-1H-indol-1-yl}methyl)phenoxy]butanoic acid 1612-[3-({2-methyl-6-(trifluoromethoxy)-3-[4-(trifluoromethoxy)benzoyl]-1H-indol-1-yl}methyl)phenoxy]butanoic acid 1623-methyl-2-[3-({2-methyl-6-(trifluoromethoxy)-3-[4-(trifluoromethoxy)benzoyl]-1H-indol-1-yl}methyl)phenoxy]butanoic acid 1633-methyl-2-[3-({2-methyl-6-(trifluoromethoxy)-3-[4-(trifluoromethoxy)benzoyl]-1H-indol-1-yl}methyl)phenoxy]butanoic acid 164(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-1H-indol-1-yl]methyl}phenoxy)propanoicacid 165(2S)-2-(3-{[3-(4-chlorobenzoyl)-2-methyl-1H-indol-1-yl]methyl}phenoxy)propanoicacid 166(2R)-2-(3-{[3-(4-methoxybenzoyl)-2-methyl-1H-indol-1-yl]methyl}phenoxy)propanoicacid 1672-(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}benzyl)butanoic acid 1682-({6-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]pyridin-2-yl}oxy)-2-methylpropanoic acid 169(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-(chloromethyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 170(2R)-2-(3-{[3-(4-chlorobenzoyl)-2-(fluoromethyl)-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1712-[(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)sulfinyl]-2-methylpropanoic acid 1722-[(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)sulfonyl]-2-methylpropanoic acid 1732-[(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)thio]-2-methylpropanoic acid 1742-[(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)thio]propanoic acid 1752-[(3-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenyl)thio]propanoic acid 176(2R)-2-{3-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 177(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic acid 178(2R)-2-{3-fluoro-5-[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 179(2R)-2-{3-[3-(4-chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]-5-fluorophenoxy}butanoic acid 180(2S)-2-(2-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 181(2R)-2-(2-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 1822-(2-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 183(2R)-2-(2-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 184(2S)-2-(2-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 185(2S)-2-(4-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 186(2R)-2-(4-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 1872-(4-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 188(2R)-2-(4-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 1892-(4-{[3-(4-methoxybenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid

TABLE 4 Compound Where R³ is Phenyl PARENT Retention MOLSTRUCTURE WEIGHTMass Spec Time 1

499.491 500(M + 1) 4.22 2

499.491 500(M + 1) 4.22 3

513.518 514(M + 1) 4.28 4

513.518 514(M + 1) 4.29 5

499.491 500(M + 1) 4.14 6

499.491 500(M + 1) 4.14 7

513.518 514(M + 1) 4.19 8

513.518 514(M + 1) 4.19 9

527.545 528(M + 1) 4.35 10

527.545 528(M + 1) 4.36 11

567.49 568(M + 1) 4.07 12

567.49 568(M + 1) 4.07 13

601.935 602(M + 1) 4.21 14

501.937 502(M + 1) 4.15 15

501.937 502(M + 1) 4 16

489.883 M + H 4.26 17

489.883 M + H 4.26 18

501.937 502(M + 1) 4.15 19

517.937 518(M + 1) 4.2 20

517.937 518(M + 1) 4.2 21

501.937 502(M + 1) 4.18 22

517.937 502(M + 1) 4.21 23

503.91 M + H 4.45 24

503.91 M + H 4.43

TABLE 4A Compound Where R³ is Phenyl 1(2S)-2-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 2(2R)-2-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 32-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 42-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 5(2S)-2-(3-{[3-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 6(2R)-2-(3-{[3-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)propanoic acid 72-(3-{[3-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 82-(3-{[3-(4-methoxyphenyl)-2-methyl-4-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 92-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 102-(3-{[3-(4-methoxyphenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-3-methylbutanoic acid 112-(3-{[3-(4-methoxyphenyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 122-(3-{[3-(4-methoxyphenyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 132-(2-chloro-5-{[3-(4-methoxyphenyl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 14(2S)-2-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 15(2S)-2-(3-{[3-(4-chlorophenyl)-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 16(2S)-2-{3-[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 17(2R)-2-{3-[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic acid 182-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 192-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 202-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)butanoic acid 212-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethyl)-1H-indol-1-yl]methyl}phenoxy)-2-methylpropanoic acid 222-(3-{[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl}phenoxy)-2methylpropanoic acid 232-{3-[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid 242-{3-[3-(4-chlorophenyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoicacid

1-34. (canceled)
 35. A method of treating one or more diseases,disorders, or conditions selected from the group consisting of (1)non-insulin dependent Type 2 diabetes mellitus (NIDDM), (2)hyperglycemia, (3) low glucose tolerance, (4) insulin resistance, (5)obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9)hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels,(12) high LDL levels, (13) atherosclerosis and its sequelae, (14)vascular restenosis, (15) irritable bowel syndrome, (16) inflammatorybowel disease, (17) Crohn's disease, (18) ulcerative colitis, (19)abdominal obesity, (20) retinopathy, (21) psoriasis, (22) high bloodpressure, (23) metabolic syndrome, (24) ovarian hyperandrogenism(polycystic ovarian syndrome), and other diseases, disorders orconditions where insulin resistance is a component, said methodcomprising the administration of an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from (a) —X-Aryl-Y-Z, and (b) —X-Heteroaryl-Y-Z, whereinAryl and Heteroaryl are unsubstituted or substituted with 1-3 groupsindependently selected from A, Aryl is phenyl or naphthyl; Heteroaryl isselected from pyridyl and quinolyl; X is selected from the groupconsisting of a bond, CH₂, CH(CH₃), C(CH₃)₂, and C₃-C₆cycloalkylidene, Yis selected from the group consisting of —CH═CH—, —CH(OH)CH(OH)—,—OCR⁷R⁸—, —SCR⁷R⁸—, and —CH₂CR⁵R⁶—; Z is selected from the groupconsisting of —CO₂H and tetrazole; A is selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkenyl, —OC₁₋₄ alkyl, and halogen,wherein alkyl, alkenyl, and —Oalkyl are each optionally substituted with1-5 halogens; R⁵, R⁶, R⁷, and R⁸ are each independently selected fromthe group consisting of H, halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, C₁-C₅alkenyl, —OC₂-C₅ alkenyl, C₃₋₆ cycloalkyl, phenyl, and —CO₂H, whereinC₁₋₅ alkyl, —OC₁-C₅ alkyl, C₂-C₅ alkenyl, —OC₂-C₅ alkenyl, C₃₋₆cycloalkyl, and phenyl are optionally substituted with 1-5 halogens, andC₃₋₆ cycloalkyl and phenyl are further optionally substituted with 1-3groups independently selected from C₁-C₃ alkyl and —OC₁-C₃ alkyl, saidC₁-C₃ alkyl and —OC₁-C₃ alkyl being optionally substituted with 1-3halogens; Or alternatively R⁷ and R⁸ may be joined to form a C₃-C₆cycloalkyl group, said C₃-C₆ cycloalkyl group being optionallysubstituted with 1-3 halogens; Or alternatively, when R¹ is—X-Phenyl-Y-Z, Y is —OCR⁷R⁸, and R⁷ is selected from the groupconsisting of H, halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, C₂₋₅ alkyl, —OC₂₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, then R⁸ may optionally be a1-2-carbon bridge connected to the phenyl ring at the position ortho toY, thereby yielding a 5 or 6-membered heterocyclic ring fused to thephenyl ring; R² is C₁-C₄ alkyl, which is optionally substituted with 1-5halogens; R³ is selected from the group consisting of (a)benzisoxazolyl, (b) benzisothiazolyl, (c) benzpyrazolyl, (d) Aryl (e)—C(═O)Aryl, (f) —C(═O)Heteroaryl, (g) —OAryl, (h) —OHeteroaryl, (i)—S(O)_(n)Aryl, and (j) —S(O)_(n)Heteroaryl, wherein R³ is optionallysubstituted with 1-3 substituent groups independently selected fromhalogen, C₁₋₃alkyl, —OC₁₋₃alkyl, and —SC₁₋₃alkyl, wherein C₁₋₃alkyl,—OC₁₋₃alkyl, and —SC₁₋₃alkyl are optionally substituted with 1-5halogens; each R⁴ is optionally selected from H, halogen, C₁-C₅ alkyland —OC₁-C₅ alkyl, wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionallysubstituted with 1-5 halogens; n is an integer from 0-2; and p is aninteger from 1 to 3; and an effective amount of one or more othercompounds selected from the group consisting of: (1) PPAR gamma agonistsand partial agonists; (2) biguanides; (3) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (4) dipeptidyl peptidase IV (DP-IV)inhibitors; (5) insulin or an insulin mimetic; (6) sulfonylureas; (7)α-glucosidase inhibitors; (8) agents which improve a patient's lipidprofile, said agents being selected from the group consisting of (a)HMG-CoA reductase inhibitors, (b) bile acid sequestrants, (c) nicotinylalcohol, nicotinic acid or a salt thereof, (d) PPARα agonists, (e)cholesterol absorption inhibitors, (f) acyl CoA:cholesterolacyltransferase (ACAT) inhibitors, (g) CETP inhibitors, and (h) phenolicanti-oxidants; (9) PPARα/γ dual agonists; (10) PPARδ agonists; (11)antiobesity compounds; (12) ileal bile acid transporter inhibitors; (13)anti-inflammatory agents; (14) glucagon receptor antagonists; (15)GLP-1; (16) GIP-1; and (17) GLP-1 analogs.
 36. The method of claim 35for treating one or more diseases or conditions selected from the groupconsisting of hypercholesterolemia, atherosclerosis, low HDL levels,high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia,which method comprises administering to a patient in need of suchtreatment a therapeutically effective amount of a combination of thecompound of Formula I, or a pharmaceutically acceptable salt thereof,and an HMG-CoA reductase inhibitor.
 37. The method of claim 36, whereinthe HMG-CoA reductase inhibitor is a statin selected from the groupconsisting of lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin.
 38. Amethod for treating or reducing the risk of developing atherosclerosisin a patient in need of such treatment comprising the administration tosaid patient of an effective amount of a combination of the compound ofclaim 35 having Formula I, or a pharmaceutically acceptable saltthereof, and an HMG-CoA reductase inhibitor.
 39. A pharmaceuticalcomposition comprising (1) a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from (c) —X-Aryl-Y-Z, and (d) —X-Heteroaryl-Y-Z, whereinAryl and Heteroaryl are unsubstituted or substituted with 1-3 groupsindependently selected from A; Aryl is phenyl or naphthyl; Heteroaryl isselected from pyridyl and quinolyl; X is selected from the groupconsisting of a bond, CH₂, CH(CH₃), C(CH₃)₂ and C₃-C₆cycloalkylidene; Yis selected from the group consisting of —CH═CH—, —CH(OH)CH(OH)—,—OCR⁷R⁸, —SCR⁷R⁸—, and —CH₂CR⁵R⁶—. Z is selected from the groupconsisting of —CO₂H and tetrazole; A is selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkenyl, —OC₁₋₄ alkyl, and halogen,wherein alkyl, alkenyl, and —Oalkyl are each optionally substituted with1-5 halogens; R⁵, R⁶, R⁷, and R⁸ are each independently selected fromthe group consisting of H, halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, C₂-C₅alkenyl, —OC₂-C₅ alkenyl, C₃₋₆ cycloalkyl, phenyl, and —CO₂H, whereinC₁-C₅ alkyl, —OC₁-C₅ alkyl, C₂-C₅ alkenyl, —OC₂-C₅ alkenyl, C₃₋₆cycloalkyl, and phenyl are optionally substituted with 1-5 halogens, andC₃₋₆ cycloalkyl and phenyl are further optionally substituted with 1-3groups independently selected from C₁-C₃ alkyl and —OC₁-C₃ alkyl, saidC₁-C₃ alkyl and —OC₁-C₃ alkyl being optionally substituted with 1-3halogens; Or alternatively R⁷ and R⁸ may be joined to form a C₃-C₆cycloalkyl group, said C₃-C₆ cycloalkyl group being optionallysubstituted with 1-3 halogens; Or alternatively, when R¹ is—X-Phenyl-Y-Z, Y is —OCR⁷R⁸, and R⁷ is selected from the groupconsisting of H, halogen, C₁-C₅ alkyl, —OC₁-C₅ alkyl, C₂₋₅ alkyl, —OC₂₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl, then R⁸ may optionally be a1-2-carbon bridge connected to the phenyl ring at the position ortho toY, thereby yielding a 5 or 6-membered heterocyclic ring fused to thephenyl ring; R² is C₁-C₄ alkyl, which is optionally substituted with 1-5halogens; R³ is selected from the group consisting of (k) benzisoxazolyl(l) benzisothiazolyl, (m) benzpyrazolyl, (n) Aryl (o) —C(═O)Aryl, (p)—C(═O)Heteroaryl, (q) —OAryl, (r) —OHeteroaryl, (s) —S(O)_(n)Aryl, and(t) —S(O)_(n)Heteroaryl, wherein R³ is optionally substituted with 1-3substituent groups independently selected from halogen, C₁₋₃alkyl,—OC₁₋₃alkyl, and —SC₁₋₃alkyl, wherein C₁₋₃alkyl, —OC₁₋₃alkyl, and—SC₁₋₃alkyl are optionally substituted with 1-5 halogens; each R⁴ isoptionally selected from H, halogen, C₁-C₅ alkyl and —OC₁-C₅ alkyl,wherein C₁-C₅ alkyl and —OC₁-C₅ alkyl are optionally substituted with1-5 halogens; n is an integer from 0-2; and p is an integer from 1 to 3;(2) one or more compounds selected from the group consisting of: (a)PPAR gamma agonists and partial agonists; (b) biguanides; (c) proteintyrosine phosphatase-1B (PTP-1B) inhibitors; (d) dipeptidyl peptidase IV(DP-IV) inhibitors; (e) insulin or an insulin mimetic; (f)sulfonylureas; (g) α-glucosidase inhibitors; (h) agents which improve apatient's lipid profile, said agents being selected from the groupconsisting of (i) HMG-CoA reductase inhibitors, (ii) bile acidsequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARα agonists, (v) cholesterol absorption inhibitors, (h) acylCoA:cholesterol acyltransferase (ACAT) inhibitors, (i) CETP inhibitors,and (j) phenolic anti-oxidants; (i) PPARα/γ dual agonists, (j) PPARδagonists, (k) antiobesity compounds, (l) ileal bile acid transporterinhibitors; (m) anti-inflammatory agents; (n) glucagon receptorantagonists; (o) GLP-1; (p) GIP-1; and (q) GLP-1 analogs; and (3) apharmaceutically acceptable carrier.
 40. The method of claim 35, whereinthe compound of Formula I is selected from the group consisting of thefollowing compounds, or a pharmaceutically acceptable salt thereof:


41. The method of claim 40, wherein the compound of Formula I has thestructure shown below, or a pharmaceutically acceptable salt thereof:


42. The method of claim 40, wherein the compound of Formula I has thestructure shown below, or a pharmaceutically acceptable salt thereof:


43. The method of claim 40, wherein the compound of Formula I has thestructure shown below, or a pharmaceutically acceptable salt thereof:


44. The method of claim 40, wherein the compound of Formula I has thestructure shown below, or a pharmaceutically acceptable salt thereof:


45. The method of claim 40, wherein the compound of Formula I has thestructure shown below, or a pharmaceutically acceptable salt thereof:


46. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof:


47. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof:


48. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof:


49. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof:


50. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof:


51. The pharmaceutical composition of claim 39, wherein the compound ofFormula I has the structure shown below, or a pharmaceuticallyacceptable salt thereof: